CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser. No. 15/753,321, filed Feb. 18, 2018, which is a § 371 national stage application of PCT/US16/47620 filed Aug. 18, 2016, which claims priority to U.S. Provisional Application 62/207,022, filed Aug. 19, 2015, all of which are incorporated herein by reference in their entirety.
SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 25, 2022, is named 2022-05-25_01308-0001-01US_Sequence_Listing_ST25.txt and is 10,989,514 bytes in size.
INTRODUCTION Methods for making antibodies have been around for over 100 years and are routinely used by the skilled artisan. See, for example, Morrison et al., Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985). Improved methods for generating antibodies have extended these initial methods and have been used to generate many of the therapeutic antibodies now being sold commercially. For example, technologies such as phage display and transgenic mice, that is, mice containing the human immunoglobulin genes, have been used to generate fully human antibodies. However, certain antigens continue to challenge a researcher's ability to raise antibodies even when using the most current techniques.
To induce a cell-mediated immune response within the human body, foreign proteins are broken down into smaller peptides, usually between 8-24 amino acids in length, and are bound to MHC molecules, for display on the surface of antigen presenting cells. The MHC-bound peptides are presented to T-cells to trigger a cell mediated immune response.
The three-dimensional (3D) structure of proteins has been implicated as a factor in proteolytic processing and presentation of epitopes (see, Carmicle et al., Molecular Immunology (2007) vol. 44: 1159-1168). Moreover, Ohkuri et al. (see, Okhuri et al., J. Immunol., (2010), vol. 185: 4199-4205) agreed that conformational stability of a protein is an immunologically dominant factor. However, there is no consensus regarding exactly how the 3D structure affects the immune response.
Delamarre et al. (see, Delamarre et al., JEM, (2006), vol 203: 2049-2055) found that less digestible forms of proteins that were less susceptible to digestion via lysosomal proteolysis were more immunogenic, and therefore, concluded that increasing protein stability improved the immune response. For example, Delamarre et al. showed that the immunogenicity of protein antigens can be improved by reducing susceptibility to proteolysis. Similarly, Mirano-Bascos et al. (see, Mirano-Bascos et al., J. of Virology, (2010), vol. 84: 3303-3311) mutated cysteine residues to prevent each of three disulfide bonds from forming, and determined that the CD4+ T-cell response was broadly reduced for all three variants. Mirano-Bascos et al. similarly concluded that global destabilization of the 3-D structure of a protein reduced antigenic presentation and led to a suppressed immune response. In other studies, such as for example, Nguyen et al., Vaccine, (2015), vol. 33: 2887-2896, outer domain disulfide bonds were deleted with the expectation that such deletions would improve antigenic presentation. Instead, a typical pattern of epitope dominance was observed and the authors concluded that it may not be possible to generate a substantially stronger immune response.
Other groups similarly conclude that protein stabilization is needed for an immune response. For example, Deressa et al., (see, Deressa et al., PLOS, (2014), vol. 9: 1-12) concluded that even minor modifications in the amino acid sequence of an antigen caused fundamental quantitative and qualitative changes in the immune response. Likewise, Porta et al. (see, Porta et al., PLOS, (2013), vol. 9: 1-8) reported that stability is needed for inducing an immune response. Other groups such as Thomas (see, Thomas et al., Human Vaccines & Immunotherapeutics, (2013), vol. 9:744-752) similarly concluded that increasing thermal stability for peptides elicited a better immune response.
In contrast, other groups such as So (see, So et al., Immunology, (2001), vol. 104: 259-268) report conflicting results. So et al. investigated the effect of crosslinking (e.g., removing cross-links and adding crosslinks) on the magnitude of in vivo T-cell responses and found that removing such crosslinks led to better antigen processing and an improved immune response. Similarly, Thai et al., J. Biol. Chem. (2004) vol. 279: 50257-50266) reported mutating surface accessible residues to decrease stability and increase conformational dynamics to increase the immunogenicity of the protein antigen. Thai et al. is also directed towards administration of single antigens.
There is no consensus on whether removing or adding crosslinks improves or inhibits antigen processing. Accordingly, it is unclear in the art as to whether increasing or decreasing protein stability would lead to an improved immune response comprising a broad, diverse array of antibodies.
Thus, there continues to be a need to develop new and improved methods of generating antibodies which can provide a different and broader repertoire of antibodies than previously obtained.
SUMMARY OF THE INVENTION This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject.
As described herein, the invention is directed towards a method of triggering an immune response wherein said method comprises designing a mixture of peptidogenic proteins derived from a starting protein, wherein the peptidogenic proteins have altered conformational dynamics as compared to the starting protein and wherein the peptidogenic proteins are similar in conformation to the starting protein, introducing the peptidogenic proteins to an animal and generating an immune response. The peptidogenic proteins can be introduced into the animals directly (by, for instance, inoculation or immunization) or can be expressed in vivo by polynucleotides that have been introduced into the animal and which encode the peptidogenic proteins. Upon expression of these peptidogenic proteins, the immune response is triggered to generate antibodies both to the peptidogenic proteins and to the original starting protein.
In preferred embodiments, the conformational dynamics of a starting protein are preferably altered by altering the thermodynamic stability of the starting protein. In further preferred embodiments, the conformational dynamics of the starting protein are altered by replacing at least one non-surface amino acid residue of a starting protein to modify the peptidogenicity of the protein. Methods of altering conformational dynamics include, but are not limited to, examining a model of the 3-D structure (experimental or predicted based on homology) of the starting protein, identifying non-surface amino acid residues of the starting protein and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic protein, and/or by comparing the pattern of conserved amino acid homology across proteins orthologous to the starting protein from different species to provisionally identify non-surface amino acid residues of the starting protein (e.g., conserved hydrophobic residues) and replacing at least one non-surface amino acid residue in the starting protein to generate the peptidogenic protein. Other methods of predicting or empirically discovering non-surface (i.e., buried) amino acid residues can also be used. These methods also include using bioinformatics tools that predict secondary structures and/or identify disordered regions of a starting protein to identify at least one non-surface amino acid residue within these structures or ordered regions for replacement, and replacing the at least one non-surface amino acid residue to generate the peptidogenic protein (see, e.g., Cheng et al., Nucleic Acids Res (2005) 33:W72-6; Huang et al. (2014), DisMeta: A Meta Server for Construct Design and Optimization In Chen editor, Structural Genomics, Humana Press pp. 3-16). In some embodiments, substitutions in disordered regions are avoided. For example, disorder predictors could be used to identify ordered/structured regions in order to select ordered regions in which to make mutations (Id.). Still other methods include using biochemical experiments to identify core residues, such as through alanine scanning of hydrophobic residues or comparable methods, to identify at least one non-surface amino acid residue within these structures or regions for replacement, and replacing the at least one non-surface amino acid residue to generate the peptidogenic protein. Accordingly, in some embodiments, residues for replacement can be identified based on known structures, and in other embodiments, residues for replacement can be identified based on conserved hydrophobic residues.
In preferred embodiments a non-surface amino acid residue is replaced with a smaller amino acid residue. In further preferred embodiments, the smaller amino acid is an alanine or glycine. In other preferred embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids are replaced in the starting protein. In still other preferred embodiments, at least 10 amino acids, at least 20 amino acids, at least 30 amino acids, at least 40 amino acids, or at least 50 amino acids are replaced in the starting protein. In still other preferred embodiments, multiple amino acid replacements are distributed across a mixture of proteins. For example, in one embodiment, to mutate 10 different residues, the starting protein is mutated 10 different times to generate 10 different peptidogenic proteins, each with a single amino acid replacement. Each of the ten proteins are mixed together to inoculate the animal. In some cases, wild type starting protein, i.e. the protein with no mutations, is part of the mixture. In further preferred embodiments, at least one disulfide bond is eliminated in the starting protein, such as, for example, replacing the cysteines with alanines, serines, and/or glycines, etc. In further preferred embodiments, both cysteines involved in the formation of the at least one disulfide bond in the starting protein are replaced with alanines, serines, and/or glycines, or preferably with alanines or glycines, etc. In further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing (a) at least one threonine with a valine, alanine, glycine or serine; or (b) at least one cysteine with alanine, valine, glycine, serine or threonine; or (c) at least one valine with alanine, glycine, leucine or isoleucine; or (d) at least one leucine with alanine, valine, glycine, or isoleucine; or (e) at least one isoleucine with alanine, valine, leucine, or glycine; or (f) at least one proline, methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine, leucine, isoleucine, or glycine; or (g) at least one aspartic acid or asparagine with glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (h) at least one glutamic acid or glutamine with aspartic acid, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (i) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (j) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (k) at least one histidine with lysine, arginine, glycine, serine, threonine, alanine, valine, glutamine, asparagine, leucine, or isoleucine; or (l) at least one alanine with a glycine; or (m) at least one residue with a non-natural amino acid; and/or (n) any of the above combinations.
In still further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (b) at least one tyrosine with phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (c) at least one phenylalanine with tyrosine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (d) at least one proline with methionine, leucine, isoleucine, valine, alanine, or glycine; or (e) at least one histidine with phenylalanine, tyrosine, methionine, isoleucine, leucine, valine, alanine, glycine, lysine, arginine, serine, threonine, asparagine, or glutamine; or (f) at least one methionine with isoleucine, leucine, valine, alanine or glycine; or (g) at least one isoleucine with leucine, valine, alanine or glycine; or (h) at least one leucine with isoleucine, valine, alanine or glycine; or (i) at least one valine with alanine, glycine, leucine, or isoleucine; or (j) at least one cysteine with alanine, valine, glycine, serine or threonine; or (k) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (l) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (m) at least one alanine with a glycine or proline; or (n) at least one serine with alanine or glycine; or (o) at least one glycine with alanine or proline; or (p) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine or isoleucine; or (q) at least one asparagine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid or glutamic acid; or (r) at least one glutamine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid, glutamic acid, or histidine; or (s) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine valine, methionine, leucine, or isoleucine; or (t) at least one threonine with valine, alanine, glycine or serine; or (u) a hydrophobic residue with a smaller, similar hydrophobic residue; or (v) at least one residue with a non-natural amino acid; or (w) any of the above combinations. A combinatorial approach may be used to determine optimal substitutions to increase peptidogenicity.
In preferred embodiments, the change in conformational dynamics of the peptidogenic protein is measured by a change in melting temperature as compared to the starting protein and/or by measuring a change in Gibbs free energy of stabilization. Preferred methods of measuring Gibbs free energy include, but are not limited to, denaturant modulated equilibrium unfolding. Preferred denaturants are urea and/or guanidinium hydrochloride. Alternatively, changes in conformational dynamics can be assayed by detecting a change in a proteolytic sensitivity assay, such as, for example, by measuring digestion with cathepsins and/or other proteases and then analyzing the mixture by mass spectrometry (MS) or sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE).
In preferred embodiments, determining whether peptidogenic proteins have a similar conformation to the starting protein can be measured by a cross-reacting antibody that binds to a 3D conformational epitope (often a discontinuous epitope) on both the peptidogenic proteins and the starting protein. Methods for measuring antibody binding include, but are not limited to an immunoprecipitation assay, surface plasma resonance, isothermal titration calorimetry, oblique-incidence reflective difference (OI-RD), western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and/or protein A immunoassays.
In further preferred embodiments, a test for measuring cross-reactivity is by a binding assay. In further preferred embodiment, the antibody binding (including a cross-reacting antibody) to a peptidogenic protein has a dissociation constant (KD) of less than or equal to 10−9M, of less than or equal to 10−8M, less than or equal to 10−7M, and/or less than or equal to 10−6M.
In preferred embodiments, the starting protein is selected from an envelope glycoprotein of the human immunodeficiency virus (HIV), HIV gp120, HIV gp41, HIV gp160, an ebola antigen, a hepatitis C virus (HCV) antigen, a hepatitis B virus (HBV) antigen, a Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) antigen, a Zika virus antigen, an influenza virus antigen, a viral antigen, a malaria antigen, a bacterial antigen, a parasitic antigen, an allergen, a venom, a toxin, or a tumor-associated antigen, a transmembrane domain protein, an ion channel protein, and/or a G-protein coupled receptor.
In further preferred embodiments, the tumor associated antigen is selected from MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A5, MAGE-A6, MAGE-A7, MAGE-A8, MAGE-A9, MAGE-A10, MAGE-A11, MAGE-A12, GAGE-I, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7, GAGE-8, BAGE-I, RAGE-1, LB33/MUM-1, PRAME, NAG, MAGE-Xp2 (MAGE-B2), MAGE-Xp3 (MAGE-B3), MAGE-Xp4 (MAGE-B4), MAGE-C1/CT7, MAGE-C2, NY-ESO-I, LAGE-I, SSX-I, SSX-2(HOM-MEL-40), SSX-3, SSX-4, SSX-5, SCP-I and XAGE, melanocyte differentiation antigens, p53, ras, CEA, MUC1, PMSA, PSA, tyrosinase, Melan-A, MART-1, gp100, gp75, alpha-actinin-4, Bcr-Abl fusion protein, Casp-8, beta-catenin, cdc27, cdk4, cdkn2a, coa-1, dek-can fusion protein, EF2, ETV6-AML1 fusion protein, LDLR-fucosyltransferaseAS fusion protein, HLA-A2, HLA-A11, hsp70-2, KIAA0205, Mart2, Mum-2, and 3, neo-PAP, myosin class I, OS-9, pml-RAR alpha fusion protein, PTPRK, K-ras, N-ras, Triosephosphate isomerase, GnTV, Herv-K-mel, NA-88, SP17, and TRP2-Int2, (MART-I), E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, alpha-fetoprotein, 13HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\170K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS, tyrosinase related proteins, TRP-1, TRP-2, and cytomegalovirus phosphoprotein 65 (pp65).
In another preferred embodiment, the peptidogenic protein is a protein that is part of a complex. For example, buried interfacial residues may be targeted for amino acid substitution, in e.g., proteins such as gp120, which is an envelope glycoprotein that forms a trimeric complex and is involved in HIV infection.
In a preferred embodiment, the mixture of polynucleotides encoding the peptidogenic proteins can be synthesized in vitro. The polynucleotides can also preferably comprise either DNA or mRNA. In preferred embodiments, the polynucleotides are in vitro transcribed (IVT) mRNA. The mRNA, including the IVT mRNA, can further comprise a poly(A) tail and/or a 5′ cap. In another preferred embodiment, the mRNA can be translated in vitro to produce the peptidogenic proteins, including by use of coupled in vitro transcription/translation (IVTT).
The mixture of polynucleotides can comprise sequences encoding different peptidogenic proteins derived from either the same starting protein or from multiple starting proteins. In further preferred embodiments, the polynucleotides can be associated with a targeting component that targets the polynucleotides to a cell or organ. Alternatively, the polynucleotides can be unassociated with a targeting component. The polynucleotides encoding the peptidogenic proteins may also comprise a vector sequence.
Mixtures of these polynucleotides as well as animals (genetically modified or not genetically modified) expressing mixtures of polynucleotides are also contemplated. In preferred embodiments, the animal is a mammal and in further preferred embodiments, the mammal is a human, a mouse, a rabbit, a llama, or a cow.
In further preferred embodiments, the method induces an immune response. The immune response can occur in vivo, ex vivo and/or in vitro.
The polynucleotides encoding the peptidogenic proteins, including, but not limited to mixtures of polynucleotides, can be delivered to the animal by injection. In preferred embodiments, the injection occurs in the muscle of the animal. The delivery of the polynucleotides to the animal can be used for vaccination purposes, in research, or antibody development.
In further preferred embodiments, the antibody produced by the described methods is recovered and isolated. In preferred embodiments, the antibody is a fully human antibody, a chimeric antibody, a single-chain antibody, a camelid antibody, a humanized antibody, a polyclonal antibody or a monoclonal antibody. In preferred embodiments, the polyclonal antibody is further fractionated into single, isolated antibody species. In other preferred embodiments, the produced antibody is affinity matured, such as, for example, by phage display, yeast display, ribosome display or by a panning technique.
Also contemplated are polynucleotides that encode the antibodies produced by the methods described herein. These antibody encoding polynucleotides can also comprise a heterologous promoter and/or a vector sequence.
The peptidogenic proteins and/or the mixtures of polynucleotides encoding the peptidogenic proteins can also be used to vaccinate a mammal. In preferred embodiments, the vaccine is a cancer vaccine, an HIV vaccine, an HCV vaccine, an HBV vaccine, an influenza virus vaccine, a MERS-CoV vaccine, a Zika vaccine, a malaria vaccine, and/or an ebola virus vaccine comprising the peptidogenic proteins.
In further preferred embodiments, the invention is a method of processing a peptidogenic protein wherein the method comprises introducing to an antigen presenting cell a peptidogenic protein, wherein the peptidogenic protein has altered conformational dynamics as compared to a starting protein and wherein the peptidogenic protein has a similar conformation to the starting protein; and permitting the antigen presenting cell to process and display T cell epitopes derived from the peptidogenic protein.
In preferred embodiments, the antigen presenting cell is a dendritic cell, a B cell, a monocyte or a macrophage. In further preferred embodiments, the method is carried out in vitro or ex vivo. In further preferred embodiments, the antigen presenting cell is transfected with a polynucleotide encoding the peptidogenic protein(s) and/or placed in contact with the peptidogenic protein(s). In further preferred embodiments the antigen presenting cell undergoes phagocytosis or pinocytosis of the peptidogenic protein(s) or polynucleotide(s).
DETAILED DESCRIPTION OF THE INVENTION Overview We describe herein a novel method of generating an immune response, including enhancing the generation of antibodies by using a protein's “peptidogenic potential” via altering the conformational dynamics of a starting protein while maintaining that protein's 3-D conformation. These peptidogenic proteins can then be used to mount an immune response, used as a vaccine and/or to generate antibodies.
Thus, the invention is directed to a method of triggering an immune response wherein said method comprises designing a mixture of peptidogenic proteins derived from a starting protein, wherein the peptidogenic proteins have altered conformational dynamics as compared to the starting protein and wherein the peptidogenic proteins are similar in conformation to the starting protein, introducing the peptidogenic proteins to an animal and generating an immune response. The peptidogenic proteins can be introduced into the animals directly (by, for instance, inoculation or immunization) or can be expressed in vivo by polynucleotides that have been introduced into the animal and which encode the peptidogenic proteins. Upon expression of these peptidogenic proteins, the immune response is triggered to generate antibodies preferably to both the peptidogenic proteins and to the original starting protein.
Introduction of the polynucleotides can occur, for example, by either directly or after first performing ex vivo transfection of dendritic cells. Additionally, polynucleotides encoding the peptidogenic proteins can be generated and introduced into an animal. The peptidogenic proteins can then be produced in the animal to generate antibodies to the peptidogenic proteins. The methods described herein have the potential to profoundly impact the immunogenicity of proteins. Preferred biophysical and biochemical properties that are altered in the protein, include, but are not limited to conformational dynamics of a protein, the thermodynamic stability, MHC-II binding, and/or the protease susceptibility of the starting protein. The methods described herein can also be used to simultaneously produce cross-reacting antibodies to different peptidogenic proteins (either derived from the same or different starting proteins) which has the potential to profoundly change the way in which antibodies are currently being generated as the repertoire of antibodies that can be obtained by a single injection in an animal has the potential to streamline antibody development and vaccination efficacy.
We have recognized that the conformational dynamics of a protein are critical for the ability of the protein to mount an immune response. The propensity of an antigen to efficiently yield peptide fragments in vivo after immunization we have termed “peptidogenicity.” Having the ability to alter the conformational dynamics of a starting protein to design a mixture of peptidogenic proteins which can be administered directly as a protein mixture or simultaneously expressed in an animal by a mixture of polynucleotides has the potential to generate a broad repertoire of antibodies with a single injection in a cost effective manner.
Thus, as disclosed herein, immunizing an animal with a mixture of peptidogenic proteins can robustly stimulate the immune system, generating stronger and/or better immune responses when placed in contact with an antigen presenting cell.
The immunization with a mixture (or combinatorial cocktail) of peptidogenic proteins is advantageous due to the complexity of the proteolytic attack on the protein antigen(s) that produces the peptides. For example, providing multiple different peptidogenic proteins having different amino acid sequences creates an environment where the “tuning mutation(s)” optimal for the production of a given peptide (T cell epitope) in the right time frame may be different from the mutations optimal for production of another peptide. For example, some cells, such as dendritic cells, mediate T-cell responses during an activation phase. If these cells are presented with antigens outside of this activation window (e.g., before or after activation) then a T-cell response may not be triggered. Thus, T-cells need to be presented with antigens at the appropriate time, which is governed by rates of protein degradation (e.g., proteolysis) in the antigen presenting cell, to trigger an immune response. By giving the antigens as mixtures, a multiplicity of different peptidogenic proteins can be endocytosed by a single cell, which theoretically maximizes the diversity of the peptides produced and displayed by that cell. Alternatively, by giving the antigens as mixtures, a multiplicity of different peptidogenic proteins can be endocytosed by multiple cells, which theoretically maximizes the diversity of the peptides produced and displayed by these cells. Additionally, the peptidogenic proteins having increased conformational dynamics may lead to an improved MHC class II binding which is expected to maximize the immune response. For example, for proteins that are relatively non-immunogenic and/or are not good vaccine components because of being too stable, and thus protease degradation is inhibited and subsequent peptide presentation is thereby impoverished resulting in attenuation of the immune response in adaptive immunity, such proteins could be altered as described herein to generate a mixture of peptidogenic proteins with altered conformational dynamics while maintaining a similar conformation as compared to the starting protein.
In preferred embodiments, a starting protein, also referred to as a test starting protein, can be systematically mutated to alter the thermodynamic stability of the starting protein, without significantly altering the three-dimensional structure of the corresponding folded protein, to generate peptidogenic proteins having increased peptidogenicity while displaying essentially the same 3D (conformational) surface epitopes as the starting protein.
Thus, increasing the immunogenicity of a starting protein by altering its conformational dynamics to produce numerous peptidogenic proteins which can then be simultaneously introduced into an animal will generate a robust immune response and has the potential to raise a broader repertoire of polyclonal antibodies which can be further fractionated (for example, by molecularly cloning via their respective encoding mRNAs) into single isolated species.
Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art, such as in the arts of peptide chemistry, cell culture and phage display, nucleic acid chemistry and biochemistry. Standard techniques are used for molecular biology, genetic and biochemical methods (see Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rd ed., 2001, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Ausubel et al., Short Protocols in Molecular Biology (1999) 4th ed., John Wiley & Sons, Inc.), which are incorporated herein by reference.
As used herein, “peptidogenicity” refers to the propensity of a protein to efficiently yield a robust set of diverse peptides which can be used to yield an immune response. Various assays exist for measuring peptidogenicity (see, for example, So et al., FIGS. 2c-d; Thai et al., FIG. 7c-f; and Delamarre et al., FIGS. 1b-c, 4b-c and 5a-b).
As used herein, a “peptidogenic protein” refers to a mutated protein that has been modified in its amino acid sequence to alter its conformational dynamics as compared to the starting protein sequence while maintaining a similar conformation to the starting protein.
As used herein, “non-surface residues” are residues that are not surface accessible with regard to the 3D structure of a protein, e.g., residues that are buried within the interior of the 3D structure of the native protein. In preferred embodiments, “non-surface” residues are defined by the method of Lee and Richards (see, e.g., Lee B et al., J. Mol. Biol. (1971); 55(3):379-IN4. doi:http://dx.doi.org/10.1016/0022-2836(71)90324-X.), where the relative solvent accessibility of the residue in the native protein is less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 5%, or 0%, or by the same method where the difference between the absolute solvent accessible surface area and the surface area in the fully extended Ala-X-Ala tripeptide (see, e.g., Gready J E et al., Protein Science. (1997); 6(5):983-98. doi: 10.1002/pro.5560060504.) is greater than 40 Å2, greater than 50 Å2, greater than 60 Å2, greater than 70 Å2, greater than 80 Å2, greater than 90 Å2, greater than 100 Å2, greater than 110 Å2, or greater than 120 Å2. In further preferred embodiments, “non-surface” residues are defined as residues with a solvent accessible surface area of less than 10 Å2, less than 5 Å2, less than 2.5 Å2, or less than 1 Å2, as calculated by a structural analysis software package familiar to those skilled in the art (e.g. UCSF Chimera (see, e.g., Pettersen E F et al., J. Comput. Chem. (2004); 25(13):1605-12. Epub 2004/07/21.), PyMol (see, e.g., Schrodinger, LLC. The PyMOL Molecular Graphics System, Version 1.8. 2015.), etc.
As used herein, a “starting protein” or “test starting protein” refers to the amino acid sequence of the “original” or “reference” protein that is used to derive the peptidogenic protein. In some examples, the “starting protein” can be a peptidogenic protein that has been further modified.
As used herein, an “immune response” refers to the humoral immune response and/or the cell-mediated immune response that is triggered by an antigen presenting cell after processing a protein. In the humoral immune response, B lymphocytes produce antibodies that react with native, unprocessed antigens. These antigen-antibody reactions may in some cases involve cell-surface antigens that activate the complement cascade, which causes the lysis of cells bearing those antigens. In the cell-mediated immune response, T lymphocytes mobilize macrophages in the presence of processed peptide antigens recognized as foreign. Activated T lymphocytes can also attack cells bearing foreign antigens directly.
As used herein, an “antigen presenting cell” refers to a cell that can break down (“process”) a protein into peptides and present the peptides, in conjunction with the MHC allele, preferably major HLA complex class I or class II molecules, on the cell surface. Examples of antigen presenting cells include, but are not limited to dendritic cells, macrophages, B cells, and monocytes.
As used herein, “conformational dynamics” is defined as the phenomena related conformational changes and flexibility of a protein structure in the spatial arrangement of atoms or groups of atoms with respect to each other in a protein molecule. Conformational dynamics include “breathing” motions and involve the vibration, bending, twisting, rotation, and other allowed modes of movement of the atoms joined by the covalent bonds in the protein molecule, governed by intrinsic restoring forces but modulated by non-covalent interactions such as hydrogen bonds, van der Waals forces, and electrostatic interactions. These motions can subtly change the geometry of the protein on a sub-picosecond timescale and can result in a vast diversity of conformational states on a time-scale of microseconds to milliseconds. Conformational molecular dynamics of proteins is often studied using computer simulations. See, for example, Shaw et al (2010) Science 330, 341. Also as used herein, the conformational dynamics of a starting protein can be altered by chemical modifications, amino acid substitutions, and other mutations such as deletions, insertion, truncations, or any combination thereof, etc. By stating that the conformational dynamics of the peptidogenic protein is varied with regard to the wild type protein, it is meant that the one or more amino acid substitutions of the peptidogenic protein results in altered conformational dynamics as compared to the wild type protein.
As used herein, “thermodynamic stability” is defined in terms of a chemical system where no or minimal energy is either released or consumed, and thus no or minimal changes in thermal energy are present and the system is in its lowest energy state under a given set of experimental conditions. Also as used herein, a “decrease in thermodynamic stability” or “decreased thermodynamic stability” means that the parameters pertaining to thermodynamic stability of the peptidogenic protein are attenuated as compared to those of the starting protein measured under the same conditions, and this decrease can be achieved in the peptidogenic protein by, but not limited to, alterations to the molecular structure of the starting protein via chemical modifications, amino acid substitutions, and other genetic mutations. Methods of measuring a decrease in thermodynamic stability are known in the art and described herein, and include protocols incorporating the measurement of parameters such as melting temperature and urea- or guanidinium hydrochloride-induced equilibrium unfolding (denaturation). These parameters are typically arrived at by monitoring the protein unfolding reaction as a function temperature or denaturant concentration under conditions of equilibrium or quasi-equilibrium. Methods for monitoring the unfolding reaction by measuring the concentration of the unfolded state relative to that of the folded state include, but are not limited to, UV absorption, fluorescence, and circular dichroism. This approach allows the calculation of a stabilization free energy (Gibbs free energy) of the mutant protein relative to the stabilization free energy of the starting protein measured under the same conditions. The difference in free energy is typically denoted by ΔΔG=ΔGmutant−ΔGstandard(e.g., wt), where ΔGmutant and ΔGstandard(e.g., wt) are the stabilization free energies of the mutant and “standard” (e.g., wt or wild type) proteins, respectively, and ΔΔG is the difference. ΔΔG>0 indicates a mutant protein that is less stable than the standard protein, and ΔΔG<0 indicates a mutant protein that is more stable than the standard protein.
As used herein, a peptidogenic protein has a “similar conformation” to a starting protein if the 3-D structure is sufficiently maintained after mutating non-surface residues of the protein (and, consequently, potentially modifying its overall conformational dynamics) to allow for an antibody to cross react with both the peptidogenic protein and the starting protein. “Cross-reactivity” can be measured by a binding assay as described herein or as is well known in the art and is measured as a “binding affinity” which is based on dissociation constants (KD), off rates (koff), and/or on rates (kon). The peptidogenic protein does not need to have an identical 3-D structure as the starting protein; just a sufficiently similar structure displaying similar 3D conformational epitopes (including discontinuous epitopes), that will allow for an antibody to recognize both proteins, even though the binding affinities may be nonidentical.
In the present invention, the term “antibody,” refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds the peptidogenic protein and/or the starting protein. As such, the term antibody encompasses not only whole antibody molecules, but also antibody fragments as well as variants (including derivatives such as fusion proteins) of antibodies and antibody fragments. Examples of molecules which are described by the term “antibody” in this application include, but are not limited to: single chain Fvs (scFvs), Fab fragments, Fab′ fragments, F(ab′)2, disulfide linked Fvs (sdFvs), Fvs, and fragments comprising or alternatively consisting of, either a VL or a VH domain. The term “single chain Fv” or “scFv” as used herein refers to a polypeptide comprising a VL domain of an antibody linked to a VH domain of an antibody. See Carter (2006) Nature Rev. Immunol. 6:243.
Additionally, antibodies of the invention include, but are not limited to, monoclonal, multi-specific, bi-specific, human, humanized, mouse, or chimeric antibodies, single chain antibodies, camelid antibodies, Fab fragments, F(ab′) fragments, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to antibodies of the invention), domain antibodies and epitope-binding fragments of any of the above. The immunoglobulin molecules of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.
Most preferably, the antibodies are human antibodies. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries and xenomice or other organisms that have been genetically engineered to produce human antibodies. For a detailed discussion of a few of the technologies for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; and 5,939,598; and Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995).
Human antibodies or “humanized” chimeric monoclonal antibodies can be produced using techniques described herein or otherwise known in the art. For example, methods for producing chimeric antibodies are known in the art. See, for review the following references: Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No. 4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494; Neuberger et al., WO 8601533; Robinson et al., WO 8702671; Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature 314:268 (1985).
The antibodies of the present invention may be monovalent, bivalent, trivalent or multivalent. For example, monovalent scFvs can be multimerized either chemically or by association with another protein or substance. A scFv that is fused to a hexahistidine tag or a Flag tag can be multimerized using Ni-NTA agarose (Qiagen) or using anti-Flag antibodies (Stratagene, Inc.).
The antibodies of the present invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for the peptidogenic protein, for more than one peptidogenic protein, for the starting protein, or they may be specific for both the peptidogenic protein and/or the starting protein and a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et. al., J. Immunol. 148:1547-1553 (1992).
The term “fragment” as used herein refers to a polypeptide comprising an amino acid sequence of at least 5 amino acid residues, at least 10 amino acid residues, at least 15 amino acid residues, at least 20 amino acid residues, at least 25 amino acid residues, at least 30 amino acid residues, at least 35 amino acid residues, at least 40 amino acid residues, at least 45 amino acid residues, at least 50 amino acid residues, at least 60 amino residues, at least 70 amino acid residues, at least 80 amino acid residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 125 amino acid residues, at least 150 amino acid residues, at least 175 amino acid residues, at least 200 amino acid residues, or at least 250 amino acid residues, of the amino acid sequence of the peptidogenic protein or starting protein. In some embodiments, a fragment may also refer to a polypeptide comprising an amino acid sequence of about 8 to 24 amino acid residues, or about 5 to 30 amino acid residues.
The term “fusion protein” as used herein refers to a polypeptide that comprises, or alternatively consists of, an amino acid sequence of the peptidogenic protein, the starting protein, and/or the antibody raised against the peptidogenic protein and an amino acid sequence of one or more heterologous peptides and/or polypeptides. For vaccine applications, the heterologous polypeptide sequence fused to the peptidogenic protein is preferably from a viral protein.
The term “host cell” as used herein refers to the particular subject cell transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. Progeny may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences or developmental steps that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.
A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar chemical nature (e.g., size, charge, steric features [e.g., beta-branched vs. non-beta-branched], polarity [hydrophilic vs. hydrophobic], aromatic vs. non-aromatic, etc.). Whether or not a particular substitution is deemed “conservative” may also depend on the structural context in the folded protein in which a substitution occurs. Amino acid side chains may be chemically similar in one respect but chemically dissimilar in another, and the context may determine which of these properties dominates in terms of how “conservative” (i.e., least disruptive) that particular substitution is. Families of amino acid residues having chemically similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine), nonpolar side chains (e.g., glycine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Some side chains have a hybrid character that is pH-dependent in physiologically relevant pH ranges. For example, histidine (pKa˜6) becomes more positively-charged (basic) below pH 6, and polar but substantially uncharged at pH 7.5 and above. Cysteine (pKa˜8.5) is substantially uncharged (and not particularly polar) below pH 8, but negatively charged (and acidic) at pH 9. The tyrosine phenolic side chain is also partially ionized and negatively charged at higher pH. Moreover, the local electrostatic environment (context) of the rest of the protein can shift these effective pH values substantially. Moreover, an acidic protein cysteine thiolate side chain can react, via thiol-disulfide exchange involving an intermediary disulfide-containing compound such as oxidized glutathione, with another protein cysteine thiol to form an intramolecular disulfide bond; such bonds are highly hydrophobic (non-polar). Additionally, both naturally occurring and/or non-naturally occurring amino acids can be used in the peptidogenic proteins.
Mutations can be introduced in a site-directed fashion or randomly along all or part of the coding sequence. Libraries of mutants can be designed to introduce a single amino acid substitution, two amino acid substitutions, three amino acid substitutions, four amino acid substitutions, and so forth, up to nineteen amino acid substitutions at a given residue site. In still other embodiments, libraries of mutants can be designed to introduce more than nineteen amino acid substitutions (including natural and non-natural amino acids) at a given residue site. In addition, libraries can be combinatorially designed to simultaneously produce multiple mutations at two sites, three sites, four sites, and so on. Following mutagenesis, the encoded protein may routinely be expressed and the conformational dynamics of the encoded protein and/or peptidogenicity can be determined using techniques described herein or by routinely modifying techniques known in the art. The resultant mutant proteins can be screened and evaluated for altered thermodynamic stability or for peptidogenicity or for similar conformation to the starting protein. Alternatively, the expressed protein “output” from the designed library can be used to immunize an animal without prior screening for protein properties.
As used herein, the “patient” or “subject suitable for treatment” may be a mammal, such as a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon, rhesus macaque), an ape (e.g. gorilla, chimpanzee, orangutan, gibbon), or a human. In other embodiments, non-human mammals, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g. murine, primate, porcine, canine, camels, llamas, or rabbits) may be employed.
Other aspects and embodiments of the invention provide the aspects and embodiments described herein with the term “comprising” replaced by the term “consisting of” and the aspects and embodiments described above with the term “comprising” replaced by the term “consisting essentially of”.
As used herein, “and/or” is to be taken as specific disclosure of each of the two or more specified features or components with or without the others. For example “A, B and/or C” is to be taken as specific disclosure of each (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C and (vii) A and B and C, just as if each is set out individually.
Methods of Altering the Conformational Dynamics of a Protein A peptidogenic protein can be generated using standard molecular biology mutagenesis techniques well known in the art. For example, the peptidogenic protein can be generated by random mutagenesis as is well known in the art, such as, for example, by error-prone PCR, random nucleotide insertion or deletion or other methods prior to recombination.
To generate the peptidogenic protein, protein engineering may be employed. Recombinant DNA technology known to those skilled in the art can be used to create peptidogenic proteins including single or multiple amino acid substitutions, deletions, insertions, or fusion proteins. Such peptidogenic proteins may be screened for those that have altered conformational dynamics while maintaining a similar conformation to the starting protein as described herein.
For example, to increase the conformational dynamics of the peptidogenic protein, the following table, Table 1, shows the average change in Gibbs free energy for exemplary amino acid substitutions in a range of proteins, derived from Tables 1 and 2 of Loladze et al., J. Mol. Biol. 320, 343-357 (2002) [note: this paper uses a non-standard convention when expressing Gibbs free energies between mutant and wild type proteins, namely using negative values to indicate destabilization (ΔΔG=AG(mutant)−ΔG(WT)); the standard convention is that positive changes indicate destabilization (ΔΔG=ΔG(WT)−ΔG(mutant), see paragraph 0040 above)]. For example, Val and Leu (and the other larger non-polar amino acid residues) can be substituted with smaller ones such as Ala, Thr, Asn, and/or Gly. In addition, the buried site of Glu in the native protein structure, can be substituted with Leu, Val, Asn, Thr, Ser, Ala, and/or Gly. The types of single site amino acid substitutions shown generally have little impact on the overall conformation of the starting protein.
TABLE 1
Amino Acid Substitution Average Gibbs Free Energy difference
(multiple positions in between mutant and wild type at core
various proteins) residues within a protein ΔΔG (kJ/mol)
Val −> Ala −12.1(±3.3)
Val −> Thr −11.3(±3.7)
Val −> Asn −21.5(±1.0)
Leu −> Ala −14.2(±4.2)
Another illustrative paper describing destabilizing mutations in the core of a protein that increase conformational dynamics is Kim et al (1993) Protein Sci. 2:588-596. In this work, the authors show that the mutations Phe22->Ala (2.1 kcal/mol), Tyr23->Ala (7.0 kcal/mol), Tyr35->Gly (5.7 kcal/mol), Asn43->Gly (6.0 kcal/mol), and Phe45->Ala (7.2 kcal/mol) destabilize bovine pancreatic trypsin inhibitor (BPTI) at pH 3.5 by the respective amounts shown in parentheses, without seriously disrupting the overall 3D structure of BPTI.
In addition, genetic deletions, insertions, inversions, repeats, and type substitutions selected according to general rules known in the art should have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided in Bowie, J. U. et al., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990), wherein the authors indicate that there are two main approaches for studying the tolerance of an amino acid sequence to change. The first method relies on the process of evolution, in which mutations are either accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selections or screens to identify sequences that maintain functionality.
As the authors state, these studies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at a certain position of the protein. For example, most buried amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Other such phenotypically silent substitutions are described in Bowie, J. U. et al., supra, and the references cited therein. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu and Ile; interchange of the hydroxyl-bearing residues, Ser and Thr; exchange of the acidic residues, Asp and Glu; substitution between the sidechain amide-bearing residues, Asn and Gln; exchange of the basic amino acids, Lys and Arg; and replacements among the aromatic residues, Phe and Tyr.
In preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one threonine with a valine, alanine, glycine or serine; or (b) at least one cysteine with alanine, valine, glycine, serine or threonine; or (c) at least one valine with alanine, glycine, leucine or isoleucine; or (d) at least one leucine with alanine, valine, glycine, or isoleucine; or (e) at least one isoleucine with alanine, valine, isoleucine, or glycine; or (f) at least one proline, methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine, leucine, isoleucine, or glycine; or (g) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, isoleucine; or (h) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (i) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (j) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (k) at least one histidine with lysine, arginine, glycine, serine, threonine, alanine, valine, leucine, isoleucine, or glutamine; or (l) at least one alanine with a glycine or proline; or (m) at least one asparagine with a glycine, alanine, serine, threonine, glutamine, aspartic acid, or glutamic acid; or (n) at least one glutamine with a glycine, alanine, serine, threonine, asparagine, aspartic acid, glutamic acid, or histidine; or (o) at least one glycine with an alanine or proline; or (p) at least one residue with a non-natural amino acid; or (q) any combination of (a)-(p). In still further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (b) at least one tyrosine with phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (c) at least one phenylalanine with tyrosine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (d) at least one proline with methionine, leucine, isoleucine, valine, alanine, or glycine; or (e) at least one histidine with phenylalanine, tyrosine, methionine, isoleucine, leucine, valine, alanine, glycine, lysine, arginine, serine, threonine, asparagine, or glutamine; or (f) at least one methionine with isoleucine, leucine, valine, alanine or glycine; or (g) at least one isoleucine with leucine, valine, alanine or glycine; or (h) at least one leucine with isoleucine, valine, alanine or glycine; or (i) at least one valine with alanine, glycine, leucine, or isoleucine; or (j) at least one cysteine with alanine, valine, glycine, serine or threonine; or (k) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (l) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (m) at least one alanine with a glycine or proline; or (n) at least one serine with alanine or glycine; or (o) at least one glycine with alanine or proline; or (p) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine or isoleucine; or (q) at least one asparagine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid or glutamic acid; or (r) at least one glutamine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid, glutamic acid, or histidine; or (s) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine valine, methionine, leucine, or isoleucine; or (t) at least one threonine with valine, alanine, glycine or serine; or (u) a hydrophobic residue with a smaller, similar hydrophobic residue; or (v) at least one residue with a non-natural amino acid; or (w) any of the above combinations. In some embodiments, hydrophobic resides are targeted for replacement.
Amino acids in the starting protein that are essential for function, conformation, and/or structure and positioned on the protein surface vs. internal can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham and Wells, Science 244: 1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for those having altered conformational dynamics while maintaining a similar conformation to the starting protein.
In an additional embodiment, the amino acid sequence of the starting protein has one or more amino acids (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or 50 amino acids) replaced with the substituted amino acids as described above (either conservative or non-conservative substitutions) to produce the peptidogenic protein. For example, substitutions in positions not involving a starting protein's activity and/or internal to the protein structure can be readily made. Sites that are critical for ligand-receptor binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992); and de Vos et al. Science 255:306-312 (1992)).
Recombinant DNA technology that employs combinatorial mutagenesis and synthetic DNA synthesis approaches known to those skilled in the art can also be used to create a peptidogenic protein including single or multiple amino acid substitutions, deletions, additions or fusion proteins. Such modified polypeptides may be then screened for altered conformational dynamics while maintaining a similar conformation as the starting protein.
Thus, a peptidogenic protein can be made where one or more amino acid residues are deleted, added, or substituted to generate peptidogenic proteins having altered conformation dynamics. For example, residues in the hydrophobic “core” of the protein can be substituted with non-polar residues having smaller side chains (supra) in order to create cavities in the core and disrupt the packing, and cysteine residues can be deleted or substituted with other amino acid residues in order to eliminate disulfide bridges (which are often found in protein cores). In some embodiments, at least one disulfide bond is eliminated in the starting protein, such as, for example, replacing the cysteines with alanines, serines, and/or glycines, etc. In further preferred embodiments, both cysteines involved in the formation of the at least one disulfide bond are replaced with alanines, serines, and/or glycines, or preferably with alanines or glycines, etc.
The peptidogenic proteins are preferably provided in an isolated form, and preferably are substantially purified. Additionally, the peptidogenic proteins would display a stable 3D conformational epitope for B-cell activation while synthesized peptides (such as by chemical synthesis) can be co-administered, which could optimize the epitopes for MHC-II presentation. Alternatively, the peptidogenic proteins and peptides can be expressed by a mixture of polynucleotides. In still other embodiments, peptidogenic proteins can be combined with a wild type starting protein and synthetic peptide(s) to elicit an immune response.
In some embodiments, the rate of polypeptide degradation may be adjusted in order to produce an optimal mix of peptides, and in the right time frame, to allow maximal diversity of the displayed peptides on the antigen presenting cells.
Immunization with mixtures (such as combinatorial cocktails) of antigens is advantageous due to the complexity of the proteolytic attack on the protein antigen(s) that produce the peptides for display. Thus, the “tuning mutation(s)” optimal for the production of a given peptide (T cell epitope) in the right time frame may be different from the mutations optimal for production of another peptide. By giving the antigens as mixtures, a multiplicity of different mutant proteins may be endocytosed by a single cell or multiple cells, which maximizes the diversity of the peptides produced and displayed by that cell.
Combinatorial immunization, in which subjects are immunized with two or more distinct antigens that have the same overall surface features (i.e. cross-reacting B-cell epitopes) but with different conformational dynamics, enriches the diversity of T-cell epitopes. This combinatorial approach, which includes hundreds or even thousands of different immunogens in a single inoculation (both protein-based and nucleotide-based) may vastly increase the B-cell epitope repertoire, since every molecule in the mix can contribute to one or more unique T-cell epitopes while maintaining a wild type-like conformation. In some aspects, because the wild-type configuration is maintained, the B-cell epitope repertoire is biased towards the most stable (and presumably wild type-like) molecules in the ensemble.
Peptidogenic Protein has a Similar Conformation as a Starting Protein The operational test of whether the peptidogenic protein has a “similar conformation to the starting protein” is whether or not a cross-reacting antibody, especially an antibody that recognizes a conformational (3D) epitope, specifically binds to both the peptidogenic protein and the starting protein. In the present invention “cross-reactivity” or a “cross-reacting antibody” is defined in terms of “binding affinity” which can be measured based on dissociation constant (KD), off rate (koff), and/or on rate (kon).
For example, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein at a dissociation constant or KD less than or equal to 5×10−6M, 10−6M, 5×10−7M, 10−7M, 5×10−8M, or 10−8M. Even more preferably, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein at a dissociation constant KD less than or equal to 5×10−9M, 10−9M, 5×10−10M, 10−10M, 5×10−11M, 10−11M, 5×10−12M, 10−12M, 5×10−13M, 10−13M, 5×10−14M, or 10−14M. The invention encompasses a dissociation constant or KD for the peptidogenic protein and/or the starting protein that is within any one of the ranges that are between each of the individual recited values. Additionally, it is specifically contemplated that the KD for the antibody that binds to a peptidogenic protein may not be identical to its KD with respect to the starting protein, and in preferred embodiments, the KD for the antibody that binds to the peptidogenic protein is less than the KD for its binding to the starting protein. It is understood that, operationally, KD in this case refers to the functional affinity of the antibody for the antigen. Functional or “apparent” affinity may be enhanced in multivalent antibodies that contain multiple interacting sites (e.g., Fab arms) that can bind to the antigen (“avidity effect”).
Additionally, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein with an off rate (koff) of less than or equal to 5×10−2 sec−1, 10−2 sec−1, 5×10−3 sec−1 or 10−3 sec−1. More preferably, a cross-reacting antibody binds to both the peptidogenic protein and the starting protein at off rate (koff) of less than or equal to 5×10−4 sec−1, 10−4 sec−1, 5×10−5 sec−1, or 10−5 sec−1, 5×10−6 sec−1, 10−6 sec−1, 5×10−7 sec−1 or 10−7 sec−1. The invention encompasses an off rate (koff) for the peptidogenic protein and/or the starting protein that is within any one of the ranges that are between each of the individual recited values. Additionally, it is specifically contemplated that the koff of the antibody for the peptidogenic protein may not be identical to the koff of the starting protein, and in preferred embodiments, the (koff) for the binding of the antibody to the peptidogenic protein is greater than the (koff) for the binding of the antibody to the starting protein.
Assays to test for the cross-reactivity are described herein or are known in the art. For example, binding assays may be performed in solution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria (e.g., U.S. Pat. No. 5,223,409), on spores (e.g., U.S. Pat. Nos. 5,571,698; 5,403,484; and 5,223,409), on plasmids (e.g., Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-1869 (1992)) or on phage (e.g., Scott and Smith, Science 249:386-390 (1990); Devlin, Science 249:404-406 (1990); Cwirla et al., Proc. Natl. Acad. Sci. USA 87:6378-6382 (1990); and Felici, J. Mol. Biol. 222:301-310 (1991)). Examples of such assays are described further below in the Examples.
Use of the Peptidogenic Protein to Generate Antibodies The peptidogenic protein can be used to generate antibodies by methods well known by the skilled artisan, such as, for example, methods described in the art. See, for instance, Sutcliffe et al., supra; Wilson et al., supra; Chow et al., Proc. Natl. Acad. Sci. USA 82:910-914 (1985); and Bittle et al., J. Gen. Virol. 66:2347-2354 (1985). If in vivo immunization is used, animals may be immunized with a peptidogenic protein and/or a polynucleotide encoding the peptidogenic protein described herein.
Animals such as rabbits, rats, mice, llamas, camels, and/or cows can be immunized with the peptidogenic protein and/or a polynucleotide encoding the peptidogenic protein. For instance, intraperitoneal and/or intradermal injection of emulsions containing about 100 micrograms of a peptidogenic protein or carrier protein and Freund's adjuvant or any other adjuvant known for stimulating an immune response may be used. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptidogenic protein antibody which can be detected, for example, by ELISA assay using free peptidogenic protein adsorbed, directly or indirectly (e.g., via a biotinylated AviTag), to a solid surface. The titer of anti-peptidogenic protein antibodies in serum from an immunized animal may be increased by selection of anti-peptidogenic protein antibodies, for instance, by adsorption to the peptidogenic protein on a solid support and elution of the selected antibodies according to methods well known in the art. Such selections could also be done using the starting protein.
Additionally, antibodies generated by the disclosed methods can be affinity matured using display technology, such as for example, phage display, yeast display or ribosome display. In one example, single chain antibody molecules (“scFvs”) displayed on the surface of phage particles are screened to identify those scFvs that immunospecifically bind to the peptidogenic protein and/or the starting protein. The present invention encompasses both scFvs and portions thereof that are identified to immunospecifically bind to the peptidogenic protein and/or the starting protein. Such scFvs can routinely be “converted” to immunoglobulin molecules by inserting, for example, the nucleotide sequences encoding the VH and/or VL domains of the scFv into an expression vector containing the constant domain sequences and engineered to direct the expression of the immunoglobulin molecule.
Recombinant expression of an antibody raised using the peptidogenic protein and/or a polynucleotide encoding the peptidogenic protein of the invention (including scFvs and other molecules comprising, or alternatively consisting of, antibody fragments or variants thereof (e.g., a heavy or light chain of an antibody of the invention or a portion thereof or a single chain antibody of the invention)), requires construction of an expression vector(s) containing a polynucleotide that encodes the antibody or fragment or variant thereof. Once a polynucleotide encoding an antibody molecule (e.g., a whole antibody, a heavy or light chain of an antibody, or variant or portion thereof (preferably, but not necessarily, containing the heavy or light chain variable domain)), of the invention has been obtained, the vector(s) for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing an antibody by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences (as well as the coding sequences for the peptidogenic protein) and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding either the peptidogenic protein or an antibody raised to the peptidogenic protein (e.g., a whole antibody, a heavy or light chain of an antibody, a heavy or light chain variable domain of an antibody, or a portion thereof, or a heavy or light chain CDR, a single chain Fv, or fragments or variants thereof), operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy chain, the entire light chain, or both the entire heavy and light chains.
The expression vector(s) can be transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce either the peptidogenic protein or the antibody that has been raised against a peptidogenic protein. Thus, the invention includes host cells containing polynucleotide(s) encoding the peptidogenic protein or an antibody raised against the peptidogenic protein (e.g., whole antibody, a heavy or light chain thereof, or portion thereof, or a single chain antibody of the invention, or a fragment or variant thereof), operably linked to a heterologous promoter. In preferred embodiments, for the expression of entire antibody molecules, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.
A variety of host-expression vector systems may be utilized to express the peptidogenic protein or the antibody raised to the peptidogenic protein. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected, with the appropriate nucleotide coding sequences, express the peptidogenic protein or the antibody raised to the peptidogenic protein. These include, but are not limited to, microorganisms such as bacteria (e.g., E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing coding sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5K promoter). Preferably, bacterial cells such as Escherichia coli, and more preferably, eukaryotic cells, are used for the expression of either the peptidogenic protein or a recombinant antibody molecule. For example, mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus is an effective expression system (Foecking et al., Gene 45:101 (1986); Cockett et al., Bio/Technology 8:2 (1990)).
In bacterial systems, a number of expression vectors may be advantageously selected depending upon the intended use. For example, when a large quantity of a protein (whether a peptidogenic protein or an antibody raised against the peptidogenic protein) is to be produced, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruther et al., EMBO 1. 2:1791 (1983)), in which the coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione. The pGEX vectors are designed to include thrombin or Factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
In an insect system, Autographa californica nuclear polyhedrosis virus (AcNPV) may be used as a vector to express a peptidogenic protein or an antibody raised against the peptidogenic protein. The virus grows in Spodoptera frugiperda cells. Coding sequences may be cloned individually into non-essential regions (for example, the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example, the polyhedrin promoter).
In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination.
Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the peptidogenic protein or an antibody raised against the peptidogenic protein in infected hosts (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 8 1:355-359 (1984)).
Specific initiation signals may also be required for efficient translation of inserted coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., Methods in Enzymol. 153:51-544 (1987)).
In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed, to this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERY, BHK, Hela, COS, NSO, MDCK, 293, 3T3, W138, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT2O and T47D, and normal mammary gland cell line such as, for example, CRL7O3O and HsS78Bst.
For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the peptidogenic protein or an antibody raised against the peptidogenic protein may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with a polynucleotide controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign polynucleotide, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the peptidogenic protein or an antibody raised against the peptidogenic protein.
A number of selection systems may be used, including but not limited to, the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthineguanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:8 17 (1980)) genes can be employed in tk−, hgprt− or aprt− cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 (Goldspiel et al., Clinical Pharmacy, 12: 488-505 (1993); Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62: 191-217 (1993); TIB TECH 11(5):155-2 15 (May; 1993)); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example; in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, N Y (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, N Y (1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley & Sons, N Y (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981).
The expression levels of a peptidogenic protein or an antibody raised against the peptidogenic protein can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York, 1987)). When a marker in the vector system expressing a peptidogenic protein or an antibody raised against the peptidogenic protein is amplifiable, an increase in the level of inhibitor present in the host cell culture will increase the number of copies of the marker gene. Since the amplified region is associated with the coding sequence, production of the peptidogenic protein or an antibody raised against the peptidogenic protein will also increase (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).
Other elements that can be included in vector sequences include heterologous signal peptides (secretion signals), membrane anchoring sequences, introns, alternative splice sites, translation start and stop signals, inteins, biotinylation sites and other sites promoting post-translational modifications, purification tags, sequences encoding fusions to other proteins or peptides, separate coding regions separated by internal ribosome reentry sites, sequences encoding “marker” proteins that, for example, confer selectability (e.g., antibiotic resistance) or sortability (e.g., fluorescence), modified nucleotides, and other known polynucleotide cis-acting features not limited to these examples.
In the case of antibodies, the host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain is preferably placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2 197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA or synthetic DNA sequences.
Once a peptidogenic protein or an antibody raised against the peptidogenic protein has been produced by recombinant expression, it may be purified by any method known in the art for purification of a protein, for example, by chromatography (e.g., ion exchange, affinity (particularly by Protein A affinity and immunoaffinity for the specific antigen), and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. Further, a peptidogenic protein or an antibody raised against the peptidogenic protein may be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.
In one example, the peptidogenic protein or the antibody raised to the peptidogenic protein described herein may be fused with the constant domain of immunoglobulins (IgA, IgE, IgG, IgM), or portions thereof (CH1, CH2, CH3, or any combination thereof and portions thereof), or albumin (including but not limited to recombinant human albumin or fragments or variants thereof (see, e.g., U.S. Pat. No. 5,876,969, issued Mar. 2, 1999, EP Patent 0 413 622, and U.S. Pat. No. 5,766,883, issued Jun. 16, 1998), resulting in chimeric polypeptides. Such fusion proteins may facilitate purification and may increase half-life in vivo. This has been shown for chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins. See, e.g., EP 394,827; Traunecker et al., Nature, 331:84-86 (1988). Enhanced delivery of an antigen across the epithelial barrier to the immune system has been demonstrated for antigens (e.g., insulin) conjugated to an FcRn binding partner such as IgG or Fe fragments (see, e.g., PCT Publications WO 96/22024 and WO 99/04813). IgG Fusion proteins that have a disulfide-linked dimeric structure due to the IgG portion disulfide bonds have also been found to be more efficient in binding and neutralizing other molecules than monomeric polypeptides or fragments thereof alone. See, e.g., Fountoulakis et al., J. Biochem., 270:3958-3964 (1995). Nucleic acids encoding the peptidogenic protein or antibodies described herein can also be recombined with a gene of interest as an epitope tag (e.g., the hemagglutinin (“HA”) tag or flag tag) to aid in detection and purification of the expressed polypeptide. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-897). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the open reading frame of the gene is translationally fused to an amino-terminal tag consisting of six histidine residues. The tag serves as a matrix-binding domain for the fusion protein. Extracts from cells infected with the recombinant vaccinia virus are loaded onto Ni2+ nitriloacetic acid-agarose column and histidine-tagged proteins can be selectively eluted with imidazole-containing buffers.
Vaccination A mixture of peptidogenic proteins and/or polynucleotides encoding the peptidogenic proteins can be used to vaccinate an animal. This vaccination may lead to the raising of antibodies to the peptidogenic proteins. A subject suitable for treatment as described above may be a mammal, such as a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon, rhesus macaque), an ape (e.g. gorilla, chimpanzee, orangutan, gibbon), or a human. In some preferred embodiments, the subject is a human. In other embodiments, non-human mammals, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g. murine, primate, porcine, canine, or rabbit animals) may be employed.
In some embodiments, the peptidogenic proteins are chimeric fusion proteins, e.g., a viral protein that has been fused to another protein, that are used for vaccines.
A vaccination strategy can be based on repetitive administration of the peptidogenic proteins and/or polynucleotides encoding the peptidogenic proteins to the subject as described herein to enable the development of memory B cells and memory T cells against the peptidogenic protein. Vaccination can be conducted either prophylactically or therapeutically. The peptidogenic proteins can be derived from either the same starting protein or from multiple starting proteins. While prophylactic vaccination strategies aim to stimulate the subject's immune system in developing preventive adaptive immunity to a pathogen, the goal of therapeutic vaccination strategy is conducted after the disease has been already established or to improve a clinical situation, present in the subject.
Proteolytic processing involves antigens such as peptidogenic proteins being processed in Antigen Presenting Cells after endocytosis and fusion of the endosome with a lysosome. The endosome then merges with an exocytic vesicle from the Golgi apparatus containing class II MHC molecules, to which the resultant peptides bind. The MHC-peptide complex then trafficks to the plasma membrane where the antigen is available for display to CD4+ T cells. Any limitation of the proteolytic processing of the peptidogenic proteins could promote a narrowing of the diversity of the peptide products, which would give the class II MHC molecules fewer options among which to select stable binding partners, and this could exacerbate the phenomenon of immunodominant determinants. Heightened immunodominance would in turn increase the proportion of non-responders in the population, because immune responsiveness is governed by the genetics of class II MHC alleles. Hence, vaccines using a mixture of peptidogenic proteins and/or polynucleotides encoding the peptidogenic proteins described herein should increase the variety of antigen peptides resulting from intra-endosomal proteolytic processing and therefore would be expected to increase the effectiveness of the vaccine.
Introduction into Animals Polynucleotides Encoding Peptidogenic Proteins
Polynucleotides encoding the peptidogenic proteins can also be directly introduced into animals. See, for example, U.S. Pat. Nos. 5,676,954; 6,875,748; 5,661,133; Sahin et al., Nat Rev Drug Discov, 2014 October; 13(10):759-80; Kariko et al., Mol Ther, 2008 November; 16(11):1833-40; Kariko et al., Nucleic Acid Res, 2011, November; 39(21):e142; U.S. Pat. No. 6,511,832. In one example, polynucleotides, such as a DNA sequences encoding a mixture of peptidogenic proteins are directly injected into a host animal and the polynucleotides enter into the nucleus to be transcribed to mRNA in order to produce the peptidogenic proteins.
Similarly, the polynucleotides can also be mRNA sequences, such as an in vitro transcribed mRNA (IVT mRNA). Essentially, synthetic mRNAs can be engineered to express peptidogenic proteins, and ideally, the mRNA is translated in the cell's cytoplasm without entering the nucleus. In the cytoplasm, the mRNA is decoded by ribosomes and is translated into the peptidogenic proteins.
In either method, the peptidogenic proteins are then processed and used to generate antibodies, much like immunization with a protein. The polynucleotides encoding the peptidogenic proteins can be synthesized using the genetic codon degeneracy and standard DNA synthesis techniques. Mixtures of different polynucleotides encoding the same peptidogenic protein, different peptidogenic proteins derived from the same starting protein, and/or different peptidogenic proteins derived from different starting proteins can be used.
Mammals that can be used to raise antibodies, include but are not limited to rabbits, rats, mice, llamas, and/or cows. The polynucleotides disclosed herein can be injected into the animals via intramuscular, intradermal, intranasal, subcutaneous, intravenous, intratracheal, and intrathecal deliveries. This method of raising antibodies allows for the concurrent production of many species of antibodies as compared to conventional methodology, substantially increasing the repertoire of antibodies produced.
Formulations A pharmaceutical composition may comprise the peptidogenic proteins described herein, polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein along with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art. Suitable materials will be sterile and pyrogen-free, with a suitable isotonicity and stability. Examples include sterile saline (e.g. 0.9% NaCl), water, dextrose, glycerol, ethanol or the like or combinations thereof. Such materials should be non-toxic and should not interfere with the efficacy of the active compound. The precise nature of the carrier or other material will depend on the route of administration, which may be by bolus, infusion, injection or any other suitable route, as discussed below. The composition may further contain auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like. Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
In some embodiments, the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins or an antibody raised to the peptidogenic protein may be provided in a lyophilized form for reconstitution prior to administration. For example, lyophilized reagents may be re-constituted in sterile water and mixed with saline prior to administration to a subject.
Additionally, “cocktails” of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are specifically contemplated. For example, a mixture of different peptidogenic proteins or polynucleotides encoding different peptidogenic proteins derived from the same starting protein can be used to mount an immune response. Alternatively, a mixture of different peptidogenic proteins or polynucleotides encoding different peptidogenic proteins derived from different starting materials may also be used to mount an immune response.
The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
Optionally, other therapeutic or prophylactic agents may be included in a pharmaceutical composition or formulation.
Treatment may be any treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition or delay of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, cure or remission (whether partial or total) of the condition, preventing, delaying, abating or arresting one or more symptoms and/or signs of the condition or prolonging survival of a subject or patient beyond that expected in the absence of treatment.
Treatment as a prophylactic measure (i.e. prophylaxis) is also included. For example, a subject susceptible to or at risk of the occurrence or re-occurrence of the disease may be treated as described herein. Such treatment may prevent or delay the occurrence or re-occurrence of the disease in the subject.
The term “therapeutically-effective amount” as used herein, pertains to that amount of the peptidogenic protein or an antibody raised to the peptidogenic protein which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
It will be appreciated that appropriate dosages of the peptidogenic protein or an antibody raised to the peptidogenic protein can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the administration. The selected dosage level will depend on a variety of factors including, but not limited to, the route of administration, the time of administration, the rate of excretion of the active compound, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of peptidogenic protein, polynucleotide encoding the peptidogenic protein, or an antibody raised to the peptidogenic protein and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve concentrations of the active compound at a site of therapy without causing substantial harmful or deleterious side-effects.
In general, a suitable dose of the peptidogenic protein or an antibody raised to the peptidogenic protein is in the range of about 100 μg to about 250 mg per kilogram body weight of the subject per day. Where the peptidogenic protein or an antibody raised to the peptidogenic protein is a salt, an ester, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals). Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the physician.
By “simultaneous” administration, it is meant that the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are administered to the subject in a single dose by the same route of administration.
By “separate” administration, it is meant that the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are administered to the subject by two different routes of administration which occur at the same time. This may occur for example where one agent is administered by infusion or parenterally and the other is given orally during the course of the infusion or parenteral administration.
By “sequential” it is meant that the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein are administered at different points in time, provided that the activity of the first administered agent is present and ongoing in the subject at the time the second agent is administered. Preferably, a sequential dose will occur such that the second of the two agents is administered within 48 hours, preferably within 24 hours, such as within 12, 6, 4, 2 or 1 hour(s) of the first agent.
Multiple doses of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins and/or an antibody raised to the peptidogenic protein may be administered. For example 2, 3, 4, 5 or more than 5 doses may be administered after administration of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, and/or an antibody raised to the peptidogenic protein. The administration of the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, and/or an antibody raised to the peptidogenic protein may continue for sustained periods of time after initial administration. For example treatment with the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein may be continued for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month or at least 2 months. Treatment with the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein may be continued for as long as is necessary to achieve a therapeutic response.
The peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein and compositions comprising these molecules may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); and parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly. Usually administration will be by the intravenous route, although other routes such as intraperitoneal, subcutaneous, transdermal, oral, nasal, intramuscular or other convenient routes are not excluded.
The pharmaceutical compositions comprising the peptidogenic protein, the polynucleotides encoding the peptidogenic proteins or an antibody raised to the peptidogenic protein may be formulated in suitable dosage unit formulations appropriate for the intended route of administration.
Formulations suitable for oral administration (e.g. by ingestion) may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
A tablet may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g. sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g. sodium lauryl sulfate); and preservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid). Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Formulations suitable for parenteral administration (e.g. by injection, including cutaneous, subcutaneous, intramuscular, intravenous and intradermal), include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilizers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the active compound in the solution is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml, from about 1 μg/ml to about 10 mg/ml, from about 10 μg/ml to about 1 mg/ml, from about 1 mg/ml to about 20 mg/ml, from about 10 mg/ml to about 120 mg/ml, or any other concentration suitable for administration of biological drugs (e.g., proteins, antibodies, etc.). The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
Compositions comprising the peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins and/or an antibody raised to the peptidogenic protein may be prepared in the form of a concentrate for subsequent dilution, or may be in the form of divided doses ready for administration. Alternatively, the reagents may be provided separately within a kit, for mixing prior to administration to a human or animal subject.
The peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, and/or an antibody raised to the peptidogenic protein may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the individual circumstances. For example, peptidogenic proteins, the polynucleotides encoding the peptidogenic proteins, or an antibody raised to the peptidogenic protein as described herein may be administered in combination with one or more additional active compounds.
Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure.
It is to be understood that the application discloses all combinations of any of the above aspects and embodiments described above with each other, unless the context demands otherwise. Similarly, the application discloses all combinations of the preferred and/or optional features either singly or together with any of the other aspects, unless the context demands otherwise.
Modifications of the above embodiments, further embodiments and modifications thereof will be apparent to the skilled person on reading this disclosure, and as such these are within the scope of the present invention. All documents and sequence database entries mentioned in this specification are incorporated herein by reference in their entirety for all purposes. The invention is further described below, with reference to the following examples.
EXAMPLES Example 1: Generating Peptidogenic Antigens To generate peptidogenic proteins, a starting protein can be modified at its core residues (e.g., one or more mutations) to alter its conformational dynamics. Multiple different peptidogenic proteins can be designed and expressed to immunize animals, such as rabbits, to generate a polyclonal antibody response. Alternatively, polynucleotides encoding the peptidogenic proteins can be directly administered to the animals to generate the peptidogenic proteins in vivo. The response will be monitored by two complementary and mutually reinforcing methods (Georgiou et al, 2014; FIG. 2): (a) purifying B cells from the blood, spleen, and bone marrow of immunized animals, isolating cDNA from mRNA encoding the variable regions of the heavy and light chains, and analyzing this repertoire via deep DNA sequencing; and (b) immunoaffinity purifying from immune sera polyclonal Fab or (Fab′)2 fragments using antigen attached to a solid support, digesting the eluted Fab/(Fab′)2s with proteases, and sequencing the resultant peptides using LC/MS/MS.
Specifically, challenging test animals (rabbits) with a variety of peptidogenic proteins (or polynucleotides encoding the peptidogenic proteins) where the conformation is similar to the starting protein, but the conformational dynamics of the peptidogenic protein is varied, can be performed. Using next-generation DNA sequencing technology, the humoral response in the animal can be comprehensively characterized. Immunoglobulin V-regions from B lymphocytes can be cloned and subjected to massively parallel deep sequencing (5-8). In conjunction with this, polyclonal antibodies from the same test animal can be purified by immunoaffinity chromatography, then protease-digested and subjected to LC-MS/MS to determine the peptide sequences (9, 10). Comparisons of these two datasets illuminate the repertoire of individual antibodies comprising the polyclonal response (9).
For example, small mammalian proteins that have been extremely well-characterized biophysically can be used as test antigens. Preferred examples, include, but are not limited to bovine pancreatic trypsin inhibitor and/or Alzheimer's amyloid precursor protein Kunitz domain. Alternatively, antigens relevant to unmet vaccine needs, such as for example, P. falciparum sporozoite antigens can also be generated and tested in this method. Additionally, optimization (or re-optimization) of synthetic vaccines with respect to conformational dynamics of the component proteins (perhaps replacing a single component with a combinatory cocktail of several versions of the same antigen with different core destabilizing mutations) can also be generated. Testing these new vaccines in clinical trials could involve monitoring of the vaccinated individuals using similar DNA sequence analyses of blood-derived B-cell V-region repertoires and proteomic characterization of immunoaffinity-purified polyclonal antibody peptides, similar to the procedures described above.
Other preferred examples of antigens that can be used according to embodiments of the invention described herein, include, but are not limited to antigens or antigens derived from, malarial polypeptides such as thrombospondin-related adhesive protein (TRAP) and/or apical membrane antigen 1 (AMA1), human immunodeficiency virus (HIV) gp120 and gp41, hepatitis C (HCV) envelope glycoproteins E1 and E2, Middle East respiratory syndrome coronavirus (MERS-CoV) Spike glycoprotein, human influenza virus hemagglutinin (HA) and neuraminidase, hepatitis B virus (HBV) capsid core, as well as antigens from related viruses that infect apes, monkeys, birds, pigs, camels, and other animals.
In preferred embodiments, any one of the P. falciparum protein antigens listed in the following Table 2 can be used as a starting protein to derive the peptidogenic protein. Additionally, multiple antigens listed in Table 2 can be used as the starting proteins to derive multiple different peptidogenic proteins to be used as a vaccine, generate an immune response, including the raising of antibodies.
TABLE 2
Predicted SP Predicted SP
Predicted Cleavage Predicted Cleavage
Gene Size Paralogs Site Gene Size Paralogs Site
MAL13P1.225 157 23/24 PFI0880C 396 25/26
PF13_0203 158 22/23 PF11_0251 421 22/23
PF11_0164 195 PFC0795C 21/22 PFC0065C 437 PF08_0022, 31/32
PF14_0015
PFL0375W 209 16/17 PFC0925W 492 30/31
PFI1270W 217 20/21 MAL13P1.121 565 34/35
PF10_0104 223 22/23 PF13_0133 590 33/34
PF13_0128 230 18/19 PFL2015W 676 27/28
PF11_0058 233 35/36 PFD0440W 693 25/26
PFA0490W 234 29/30 PFC0330W 699 26/27
PF07_0087 244 26/27 PFD0430C 840 24/25
PFB0570W 250 21/22 PF14_0462 851 PFC0550W 28/29
PF13_0180 258 PFL0740C 19/20 PF07_0100 1032 35/36
PF11_0065 282 23/24 MAL7P1.23 1183 30/31
PF14_0678 287 21/22 PFL1835W 1188 26/27
PF13_0125 292 19/20 PF07_0047 1229 PFF0940C 35/36
PF13_0141 316 PFF0895W 20/21 PF14_0250 1320 28/29
PF14_0117 327 PFI1775W, 22/23 PFE0905W 1379 24/25
PFL2530W
PF11_0098 343 26/27 PFA0180W 1472 31/32
PF14_0660 358 23/24 PFL1210W 1696 25/26
PFD0240C 378 20/21 PF14_0363 1922 26/27
PFE0080C 398 21/22 PFB0400W 2508 34/35
PFA0660W 402 PFB0090C, 34/35 PFI0920C 577 26/27
PFB0595W,
PFE0055C
PF11_0352 423 23/24 PF14_0094 768 22/23
PF11_0055 424 21/22 PFA0125C 1567 26/27
PFB0475C 446 22/23 PF10_0372 120 25/26
PF11_0302 452 21/22 PFL2315C 137 28/29
PFA0210C 466 23/24 MAL13P1.271 181 36/37
PF07_0089 467 16/17 MAL7P1.31 236 20/21
PF14_0060 475 16/17 PF10_0317 263 PF14_0653 35/36
MAL8P1.17 483 24/25 PF07_0070 322 19/20
MAL7P1.77 522 23/24 MAL7P1.64 357 28/29
PF11_0099 540 33/34 PFI0935W 370 21/22
PF07_0068 546 22/23 PFA0160C 434 22/23
PF13_0201 574 25/26 PFB0465C 457 27/28
PF07_0094 579 17/18 PF10_0208 627 23/24
PF07_0006 594 MAL8P1.143 22/23 PFB0760W 686 25/26
PFL0770W 618 PF07_0073 20/21 MAL13P1.206 687 26/27
PFI1645C 642 PF13_0262 18/19 PF14_0541 717 15/16
PF14_0166 674 25/26 PFL0790W 870 21/22
PFE0815W 681 24/25 PFL2410W 1039 24/25
PF11_0174 700 27/28 PF14_0440 1191 23/24
PFE0475W 722 PFB0525W 21/22 PF11_0333 1503 25/26
PF11_0074 743 17/18 PF10_0242 1541 20/21
PFL1385C 743 23/24 PFC0590C 1816 20/21
PF14_0102 782 22/23 PF14_0342 1898 27/28
PF11_0212 791 20/21 MAL7P1.92 2543 PFI0550W 22/23
PF07_0129 811 21/22 PF14_0593 1357 18/19
PFL2570W 816 22/23 MAL13P1.49 144 24/25
PFL1070C 821 28/29 MAL13P1.172 260 26/27
PFB0695C 888 32/33 PF08_0006 272 19/20
PF11_0175 906 PF08_0063 26/27 PFD1035W 328 37/38
MAL13P1.22 912 15/16 PF11_0052 336 24/25
PFL0035C 926 27/28 MAL13P1.79 383 19/20
PFI0685W 955 18/19 PF10_0295 426 23/24
PFD0425W 984 21/22 PFL1745C 459 22/23
PF14_0293 992 24/25 PF14_0677 467 24/25
PF14_0344 993 20/21 PFL0600W 558 23/24
PFL0560C 1024 20/21 PF08_0108 573 PF14_0281 26/27
PF07_0035 1248 20/21 PF08_0081 577 18/19
PFL1675C 1256 21/22 PF14_0620 858 25/26
PFC0435W 1294 19/20 PFE0710W 867 21/22
PFI1445W 1364 19/20 PF11_0270 1013 20/21
PF13_0354 1408 23/24 MAL7P1.149 1051 19/20
PFC0110W 1416 MAL7P1.229, 24/25 PFC0810C 1119 22/23
PFA0125C,
PFD1155W
PFC0120W 1417 24/25 PF14_0249 1169 25/26
PF08_0078 1419 20/21 PF13_0116 1258 19/20
PF14_0614 1502 16/17 MAL13P1.60 1260 25/26
PF14_0051 1515 26/27 PF11_0246 1336 23/24
PF11_0076 1988 22/23 PFL2505C 2215 21/22
MAL13P1.262 2006 21/22 PFB0405W 3135 20/21
PFC0640W 2114 26/27 PF11_0256 608 17/18
PFL2520W 2792 MAL13P1.176, 24/25 PF08_0047 613 28/29
PF13_0198
PFC0282W 116 23/24 PFC0835C 440 22/23
PF08_0004 137 25/26 PFI0605C 446 20/21
PF11_0224 162 22/23 PF10_0127 499 16/17
PF13_0272 208 22/23 PF11_0344 622 24/25
MAL13P1.171 211 20/21 PF10_0130 628 25/26
PFE1340W 214 27/28 PFL2395C 639 PF14_0428 28/29
PF14_0369 235 20/21 PF08_0008 738 21/22
PF14_0178 259 22/23 PF14_0201 966 22/23
PFL0870W 352 24/25 PFI1475W 1720 19/20
PFC0210C 397 18/19 PF13_0182 1838 26/27
PFI0500W 432 28/29 PF14_0495 2189 20/21
PF11_0069 276 25/26 PF13_0277 2068 22/23
PFD0355C 286 32/33
To alter the conformational dynamics of a starting protein, the following changes in Gibbs Free Energy, shown in Table 3 below, can be considered:
TABLE 3
Amino Acid Substitution Average Gibbs Free Energy difference
(multiple positions in between mutant and wild type at core
various proteins) residues within a protein ΔΔG (kJ/mol)
Val −> Ala −12.1(±3.3)
Val −> Thr −11.3(±3.7)
Val −> Asn −21.5(±1.0)
Leu −> Ala −14.2(±4.2)
As discussed in Loladze et al (J. Mol. Biol. 320, 343-357 (2002)), the following amino acid substitutions can decrease the thermodynamic stability (e.g., reflected in the Gibbs free energy) and alter the conformational dynamics of a starting protein. For example, Val and Leu (and other larger non-polar amino acid residues) can be substituted with smaller ones such as Ala, Thr, Asn, and/or Gly. In addition, the buried site of Glu in the starting protein, can be substituted with Leu, Val, Asn, Thr, Ser, Ala, and/or Gly. These single site amino acid substitutions are expected to generate peptidogenic proteins with lower stability but a similar conformation to the starting protein.
Alternatively, the conformational dynamics of the starting protein is altered by replacing (a) at least one threonine with a valine, alanine, glycine or serine; or (b) at least one cysteine with alanine, valine, glycine, serine or threonine; or (c) at least one valine with alanine, glycine, leucine or isoleucine; or (d) at least one leucine with alanine, valine, glycine, or isoleucine; or (e) at least one isoleucine with alanine, valine, leucine, or glycine; or (f) at least one proline, methionine, phenylalanine, tyrosine, or tryptophan with alanine, valine, leucine, isoleucine, or glycine; or (g) at least one aspartic acid or asparagine with glycine, serine, threonine, alanine, valine, leucine, isoleucine; or (h) at least one glutamic acid or glutamine with aspartic acid, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (i) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (j) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine, or isoleucine; or (k) at least one histidine with lysine, arginine, glycine, serine, threonine, alanine, valine, glutamine, asparagine, leucine, or isoleucine; or (l) at least one alanine with a glycine; or (m) at least one residue with a non-natural amino acid; and/or (n) any of the above combinations.
In still further preferred embodiments, the conformational dynamics of the starting protein is altered by replacing: (a) at least one tryptophan with tyrosine, phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (b) at least one tyrosine with phenylalanine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (c) at least one phenylalanine with tyrosine, methionine, histidine, isoleucine, leucine, valine, alanine or glycine; or (d) at least one proline with methionine, leucine, isoleucine, valine, alanine, or glycine; or (e) at least one histidine with phenylalanine, tyrosine, methionine, isoleucine, leucine, valine, alanine, glycine, lysine, arginine, serine, threonine, asparagine, or glutamine; or (f) at least one methionine with isoleucine, leucine, valine, alanine or glycine; or (g) at least one isoleucine with leucine, valine, alanine or glycine; or (h) at least one leucine with isoleucine, valine, alanine or glycine; or (i) at least one valine with alanine, glycine, leucine, or isoleucine; or (j) at least one cysteine with alanine, valine, glycine, serine or threonine; or (k) at least one aspartic acid with glutamic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (l) at least one glutamic acid with aspartic acid, glutamine, asparagine, glycine, serine, threonine, alanine, valine, leucine, or isoleucine; or (m) at least one alanine with a glycine or proline; or (n) at least one serine with alanine or glycine; or (o) at least one glycine with alanine or proline; or (p) at least one lysine with arginine, histidine, glycine, serine, threonine, alanine, valine, methionine, leucine or isoleucine; or (q) at least one asparagine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid or glutamic acid; or (r) at least one glutamine with glycine, alanine, serine, threonine, valine, leucine, isoleucine, glutamine, aspartic acid, glutamic acid, or histidine; or (s) at least one arginine with lysine, histidine, glycine, serine, threonine, alanine valine, methionine, leucine, or isoleucine; or (t) at least one threonine with valine, alanine, glycine or serine; or (u) a hydrophobic residue with a smaller, similar hydrophobic residue; or (v) at least one residue with a non-natural amino acid; or (w) any of the above combinations. A combinatorial approach may be used to determine optimal substitutions to increase immunogenicity.
Example 2: Peptidogenic Proteins of Bovine Pancreatic Trypsin Inhibitor Bovine pancreatic trypsin inhibitor (BPTI) is an extremely well-characterized small protein, on which there is a substantial body of literature describing its folding, structure, activity, thermodynamic properties, expression properties, and protease specificities (15). Our own lab was the first to express recombinant BPTI and engineer its properties using site-directed mutagenesis (16, 17). Wild type BPTI has three disulfide bonds, cross-linking disulfides 14-38, 30-51, and 5-55; the 14-38 disulfide is on the surface, and the other two disulfides are deeply buried in the hydrophobic core of the protein. Mutations of any one of these disulfides by replacing the two disulfide cysteines with alanine residues destabilizes the BPTI molecule (18). All possible combinations of disulfide bond mutants of BPTI have been made by ourselves and by others, and all are markedly destabilizing. Importantly, where it has been examined, for all combinations of mutants of BPTI that knock out one or two native disulfide bonds, the protein nevertheless maintains a similar three-dimensional structure and trypsin inhibitor activity comparable to wild type BPTI (19-22) Therefore, despite stability differences manifested by Tms ranging from >100° C. to <40° C., the wild type molecule and its disulfide mutants all display similar, if not virtually identical 3D conformational epitopes. For example, at 40° C. the mutant protein would be almost 50% unfolded at body temperature, and at >100° C. (higher than the boiling point of water) the wild type protein is among the most thermostable proteins known.
TABLE 4
Mutants of BPTI that knock out one or more of the native
disulfide bonds or core residues while preserving 3D structure
BPTI variant Sequence
wild type RPDFC LEPPY TGPCK ARIIR YFYNA KAGLC QTFVY GGCRA
KRNNF KSAED CMRTC GGA (SEQ ID NO.: 919)
[C14A, C38A] RPDFC LEPPY TGPAK ARIIR YFYNA KAGLC QTFVY GGARA
KRNNF KSAED CMRTC GGA (SEQ ID NO.: 920)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA
K15A KRNNF KSAED CMRTC GGA (SEQ ID NO.: 921)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YAYNA KAGLC QTFVY GGARA
K15A, F22A KRNNF KSAED CMRTC GGA (SEQ ID NO.: 922)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFANA KAGLC QTFVY GGARA
K15A, Y23A KRNNF KSAED CMRTC GGA (SEQ ID NO.: 923)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA
K15A, N43G KRGNF KSAED CMRTC GGA (SEQ ID NO.: 924)
[C14A, C38A], RPDFC LEPPY TGPAA ARIIR YFYNA KAGLC QTFVY GGARA
K15A, F45A KRNNA KSAED CMRTC GGA (SEQ ID NO.: 925)
For our immunological experiments with BPTI, since we are interested in protease digestion and peptide generation in vivo from the antigen, we will make the BPTI mutants described in Table 4. Mutated residues are underlined, cysteine residues are shown in bold. These consist of wild type BPTI with the surface disulfides 14-38 mutated to alanine, which has been shown to confer increased stability to reducing agents. The BPTI mutants will also be made in the [Lys15→Ala] background. The Lys15-Ala mutation ablates the P1 residue side chain and reduces BPTI's affinity towards trypsin and other proteases by as much as 107-fold, rendering it essentially inactive as a protease inhibitor (23). Additional mutations within the core of the protein (e.g. F22A, Y23A, N43G, F45A) serve to destabilize the protein and alter conformational dynamics to varying degrees while still maintaining a 3D structure comparable to wild type BPTI. This table is intended to be non-limiting with respect to present invention embodiments.
Analogous mutations can be made in the Alzheimer's amyloid precursor protein Kunitz inhibitor (APP-KI), which is a human protease inhibitor homologous to BPTI. APP-KI has a relatively low isoelectric point (pI) and so, unlike BPTI, it should be electrostatically nearly neutral in charge at lysosomal pH. Like BPTI, APP-KI has previously been expressed and characterized in terms of folding, activity, and 3D structure, and it has three disulfide bonds precisely homologous to those found in BPTI.
We will express the mutants both with and without flanking tag sequences. Tags we have used to vary solubility include the calmodulin binding peptide (CBP) tag, which is highly soluble, to the TrpLE tag, which is highly insoluble (24). In a particularly favored construct, however, we use a tripartite tag: AviTag-hexaHis-TEV protease cleavage site. This tag confers intermediate solubility, can by biotinylated using the BirA biotin ligase (25), allows binding to a HisTrap column for purification and/or on-column refolding (Campbell and Anderson, in preparation), and can be cleaved off the antigen if necessary. The antigen can be used to immunize animals either without the tag (i.e., after TEV cleavage) or with the tag intact followed by subtractive depletion of anti-tag antibodies (S. Blackshaw and D. Eichinger, personal communication).
Example 3: Preferred Targets of the Present Invention As used herein a “Target” is a specifically selected protein disclosed in Table 5 that can be modified to have an improved peptidogenicity as described herein. Column 1 lists the SEQ ID NO. corresponding to the sequence provided in the Sequence Listing. Column 2 lists the “Protein Name” of each Target and Column 3 provides the “UniProt Reference Number” which is a unique “cataloging” number (UniProt Reference Numbers provide a mapping of a proteome to a reference genome assembly, e.g., as produced by the Genome Reference Consortium (GRC)) used in the art that provides publicly known and established descriptions of both the function, expression and sequence information for each Target listed in Column 2. This public information (retrieved from the UniProt database (http://www.uniprot.org) on Aug. 10, 2016) including the sequence information corresponding to each Target, is herein incorporated by reference in its entirety. The Sequence Listing and Table 5 describes the positions of the specific residues in each target protein where mutations can be made to generate the corresponding peptidogenic proteins along with the specific amino acids that can be substituted at each position. In preferred embodiments, multiple substitutions can be made in each target protein at the recited positions in the Sequence Listing and as shown in Table 5. In further preferred embodiments, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more of the residues listed in the Sequence Listing and/or Table 5 for each target protein, in any combination, can be changed in the respective starting Target proteins listed in Column 2 using the amino acid specified in the Sequence Listing and/or as described in the last two paragraphs of Example 1. By spreading the mutations over multiple positions and/or target proteins, and by mixing these mutated molecules together, an immunization cocktail can be created.
TABLE 5
TARGETS
Exemplified Sites of Mutations to Generate Peptidogenic Protein
SEQ ID NO. Protein Name/Strain UniProt ID No. (Each position can be substituted alone or in any combination with any of the other listed amino acid positions.)
1 Hemagglutinin [Cleaved into: Hemagglutinin A4GCL9 V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, I74, A75, W77, L78, L79, C84, L87, W93,
HA1 chain; Hemagglutinin HA2 chain]/strain Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A151, A152, C153, H155, L165, L166, W167, L168, L178, V190, L191,
A/USA: Phila/1935 H1N1 V192, L193, W194, V196, H197, H198, Y209, Y215, V216, V218, V219, Y223, M244, Y246, Y247, L250, L251, I257, F259,
A261, L265, I266, A267, Y270, A271, F272, A273, L274, F278, I282, I283, C292, C296, A302, I303, H313, I317, V324, L329,
M331, V332, A349, M361, Y366, A388, I389, A440, L452, V459, L462, V466, L470, C481, H486, C488, C492, M493
2 Proprotein convertase subtilisin/kexin A8T655 V80, A95, L98, A102, F122, V124, A134, I143
type 9 (EC 3.4.21.—)
3 Plasminogen (EC 3.4.21.7) B2R7F8 Y193, W209, C234, W244, C245, F246, C257, I259
4 cDNA FLJ60453, highly similar to B4DEZ9 V80, L98, A102, F122, V124, A134, I143
Proprotein convertase subtilisin/kexin
type 9 (EC 3.4.21.—)
5 Receptor protein-tyrosine kinase B4DTR1 V474, I476, A495, I512, C513, V521, L530, V534, L546, L547, W549, C550, I553, A554, M557, L560, L565, V566, H567,
(EC 2.7.10.1) L570, A571, A572, V575, V577, V583, I585, A591, A614, F623, V629, W630, Y632, V634, V636, L639, M640, I655, L659,
I670, V675, M679, C682, W683, F693, F700, M703, V711
6 Interleukin-4 D4HNR6 L31, I34, L38, C48, C70, A72, A73, L76, C89, H100, L107, L110, L114, A118, L133, F136, L140, M144
7 Cell wall-binding repeat protein/NAP07 D5RWT1 F32, F51, F53, F73, A74, F104, F124, A129, A132, F143, F164, A165, F195, F215, A220, A223, F237
8 Insulin, isoform 2 F8WCM5 L35, A38, L39
9 Fusion glycoprotein F0 G8EJ09 L204, I206, I214, S215, I233, V247, M251, L257, I261, M274, I280, V281, Y299, V301, L303, C313, C333, C343, V349,
F352, V365, F366, C367, C382, A412, I413, V414, C416, C422, A424, V442, V450
10 TcdA I6YE93 F2585, A2593, F2604, F2625, A2626, F2656, F2676, A2681, A2684, F2698
11 Spike glycoprotein/isolate K9N5Q8 C30, F40, W44, I48, A53, Y58, Y64, I67, L74, Y85, F101, Y105, F112, V117, I120, A123, A124, I132, Y144, V153, L169,
United Kingdom/H123990006/2012 (HCoV-EMC) V170, L172, C176, A182, Y184, C185, C195, F232, C237, F239, Y243, W253, F254, I256, V263, L265, M278, F279, A282,
I290, Y292, Y293, I300, A309, A312, F313, Y314, Y316, L318, V329, A336, C339, L347, C349, Y351, F354, V360, Y361,
F366, A368, C383, F404, C407, Y409, L411, L414, L415, L417, V420, F423, C425, A434, C437, Y438, F446, A461, I464,
F467, Y469, C478, A482, Y497, C503, I573, Y577, V584, C585, C603, Y606, V616, F617, C620, V631, Y632, Y648, Y649,
C650, C654, V655, V657, V659, V661, I662, Y663, A671, L673, V677, C679, L697, L707, V711, C713, V724, C727, L729,
L731, L735, C736, A737, V770, I782, F786, I795, V802, C806, V810, C811, C817, L821, Y824, F827, C828, L835, L893,
L894, F895, V898, Y909, C912, L923, C925, V934, L935, Y947, W960, A968, F972, Y978, V989, L990, I997, F1001, A1004,
A1007, F1012, A1018, V1026, A1030, A1032, L1033, L1036, L1040, F1044, A1046, I1047, A1049, I1054, L1058, A1065,
I1067, L1070, I1071, L1075, L1078, A1080, L1086, V1103, C1106, V1107, F1116, C1117, I1123, V1127, A1130, L1134,
F1136, Y1141, L1155, C1156, A1166, Y1171, F1172, W1184, Y1192, I1197, V1209, Y1211, L1223, L1260, L1262, M1266,
L1276, Y1280, I1281, C1320, C1323, C1327
12 Serine/threonine-protein kinase Sgk1 O00141 A115, V126, F158, F166, L172, F174, V175, L184, A199, Y202, A203, A204, I206, A207, A209, L210, L223, I228, L230,
(EC 2.7.11.1) I236, L238, A265, V278, W280, W281, C282, L283, A285, V286, L287, M290, A324, L327, L328, L331, I349, F355, L363
13 AP-4 complex subunit mu-1 O00189 V187, L189, V191, L195, I199, V210, I214, L216, M226, I228, L230, F234, V250, L270, V281, M282, Y284, L286, F296,
L311, V313, L315, L317, C319, A327, V330, L332, L334, L347, W363, L365, V368, M380, A405, L407, F409, L411, L419,
Y449
14 Toll-like receptor 4 O00206 Y38, C40, L59, L61, L69, F74, F77, L80, L83, L85, C88, I90, I93, A97, Y98, L101, L104, L107, L109, I114, A121, F122, L125,
L128, L131, A133, L141, I146, L149, L152, L155, V157, A158, I162, F165, L167, F171, L174, L177, L180, L182, I187, I190,
L195, V197, L198, L203, L206, L208, L210, M215, I218, A222, F223, I226, L228, L231, L233, M243, C246, I247, L253, V255,
L258, L260, F272, A276, L277, L280, F288, L290, Y296, L297, I300, L303, F304, L307, V310, F313, L315, V318, I320, V323,
F326, F330, W332, L335, L337, C340, F342, L348, L350, L353, L356, F358, G363, L372, L375, L378, L380, L385, F387, C390,
C391, F396, L401, L404, L406, I412, M414, F418, L421, L424, L427, F429, M437, V442, F443, L446, L449, I450, L452, I454,
V461, I466, F467, L470, L473, L476, M478, F483, L488, F492, L495, L498, L501, L503, C506, L508, A515, F516, L519, L522,
V524, L525, M527, F532, F533, L535, Y540, L543, L546, L549, Y551, I556, L571, L574, L576, F581, F590, L591, I594, L600,
M607, V620
15 Tumor necrosis factor receptor superfamily O00220 C132
member 10A
16 Agouti-related protein O00253 C94, C119
17 Tubby-related protein 1 O00294 V295, C307, L309, L326, L337, I352, I367, L370, V381, F382, L403, A404, A405, V406, V423, I424, I425, I437, L446,
L461, I493, V503, L504, F506, F514, L516, Y518, L522, C523, A524, L525, A527, F528, A529, I530, A531, L532, L539
18 Tumor necrosis factor receptor superfamily O00300 C41, C44, C65, C124
member 11B
19 Krev interaction trapped protein 1 O00522 A10, V12, A13, V14, I15, Y28, Y33, I35, L36, L37, L54, I68, V72, A108, L110, I112, V113, L135, L152, M156, L157,
L160, L164, I174, L292, H293, A296, L304, A323, I325, H326, A328, C329, A336, L340, C346, A362, A363, I370, V371,
L374, C396, A407, I424, V434, V444, I447, I463, I465, W487, L491, L508, I522, A527, I528, I530, L531, A535, L539,
A546, L551, I552, L554, A555, L557, L558, L559, H571, I584, V585, L590, A594, I601, Y605, L621, F625, L626, C629,
I632, V658, V660, V662, L667, H668, L669, L670, F697, I699, V710, A715, V718, L722, L725
20 C-C motif chemokine 21 O00585 L63, F64, C75, A76, V83
21 Lysosomal alpha-mannosidase O00754 A241, Y306
22 Receptor-type tyrosine-protein phosphatase T O14522 F74, M75, V77, A88, L90, L92, H101, F105, L120, V122, V124, V135, A149, L151, A152, I153, Y161, V163, F165, I177,
A178, V179, V184, F211, C213, L227, A250, V252, Y265, C267, V268, I269, V277, A281, L305, I307, V325, I358, L362,
L403, L405, C417, V424, L449, I458, L460, L462, L464, I502, I504, Y519, I521, F553, Y562, F564, I566, A568, V578
23 Tumor necrosis factor receptor superfamily O14763 C81, C139
member 10B
24 Tripeptidyl-peptidase 1 O14773 L49, F51, A52, L61, V65, L80, L82, V85, A86, V89, V99, A105, F119, C122, L124, I126, A129, L133, F138, V150, Y157,
L159, V167, F169, V170, L173, V200, Y209, A226, C227, A228, F230, L240, F243, V277, Y279, L280, M281, A283, A285,
I287, F304, L305, W307, L308, V320, H321, V323, Y336, I337, V340, L344, A347, A348, A349, L355, F356, A363, F378,
A380, V385, V388, F397, V404, V426, A448, V452, A453, A454, L455, Y459, V461, V462, V471, A476, V480, F481, I484,
L485, L487, I488, V518, H523, C526, F536, V545, L556, L560
25 Tumor necrosis factor ligand superfamily O14788 L168, I170, L184, L206, V208, Y214, L216, A218, I220, F222, L238, V240, V242, L283, I289, I291, V293, A310
member 11
26 Growth/differentiation factor 8 O14793 C281, C282, C372, C374
27 Ras-related protein M-Ras O14807 L11, Y14, L16, V17, V18, V19, V24, L29, F33, V39, I56, A61, I62, L63, V65, L66, A69, M77, M82, F88, L89, I90, V91, Y92,
V94, V103, F106, I110, V113, F119, M121, I122, L123, V124, A125, I136, A145, A157, V164, A167, F168, L171, V172
28 Tumor necrosis factor O14836 C89, C100, A101
receptor superfamily member 13B
29 Interferon regulatory factor 6 O14896 W449
30 Natural cytotoxicity triggering receptor 3 O14931 A35, L37, C39, A49, F56, H89, A91, I95, V98, I105, Y106, C108, V110, V112, L125
31 Peripheral plasma membrane protein CASK O14936 F8, C15, V26, C29, V40, V45, F48, L59, L69, I74, L77, L87, M89, V90, F91, L99, C100, I103, Y113, A118, M122, I125,
L126, A128, L129, C132, I137, I138, H139, V142, C146, V147, L148, L149, V158, L160, A166, A187, V191, V202, W203,
C205, V207, I208, L209, F210, I211, L212, L213, F227, I230, W242, A249, L252, V253, M256, V267, A270, W275,
L276, L295, A310, V312
32 Cyclin-G-associated kinase O14976 L40, V42, A57, L68, L71, I82, L92, I98, I107, L122, L130, C145, V148, L149, I151, F152, C156, A158, V159, M162,
(EC 2.7.11.1) H171, L179, L181, I187, L189, F192, I198, I246, L249, L253, L256, F288, I292, M295, V309, L313, A317, I328, F525,
V640
33 Synapsin-3 O14994 L94, L95, V96, I97, W104, F126, C139, V141, I162, L163, V164, V181, V192, L211, F223, V226, V246, V247, V261,
F267, V273, V274, A281, I295, A304, Y305, W335, V336, C339, I348, C349, A350, V351, A353, I363, M371, M385, A386,
V389
34 Spectrin beta chain, non-erythrocytic 2 015020 F63, W66, V67, L71, L81, L85, L91, L92, L94, L95, V119, A122, L123, L126, L133, I141, V142, L152, V153, I156, I157,
I162, I165, L182, C186, V198, F201, W205, A210, F211, A213, I214, V215, L228, H234, L237, A240, F241, A244, L253,
L254, V259, I269, I270, Y272, V273, A274, Y276, Y277, L2225, A2238, V2246, C2248, L2250, L2255, F2257, L2278, V2295,
F2296, L2298, F2308, A2310, W2319, V2323, A2326
35 Niemann-Pick C1 protein O15118 W27, V59, C63, L73, C74, C75, L80, L94, C97, C100, L104, L107, C113, L121, V141, L144, Y146, V148, F152, A153, M156,
A159, C160, V163, A172, L173, C177, W189, I190, F194, C227, C243, L408, I410, F431, L435, V443, L444, L446, I450,
V462, L464, I467, C479, I481, V484, L485, Y487, F488, L495, A507, H510, H512, C516, C533, V541, L545, V546, L547,
A558, L561, I563, F565, V567, A580, W583, F587, L649, L656, A659, L720, L724, V727, F763, A1035, F1100, A1124, M1138,
M1228
36 Laminin subunit alpha-5 O15230 L273
37 Phosphomannomutase 2 O15305 L8, C9, L10, F11, L17, M28, F31, L32, L35, I41, V43, V44, V52, L56, V60, Y64, V67, F68, L73, A75, I87, L99, C103,
M126, L127, V129, I132, F144, F157, L161, I178, F180, V182, C192, L193, V196, F206, F207, I220, C241
38 Phosphatidylinositol 3,4,5- O15357 A31, L34, L35, F44, L45, V46, A55, L58, C59, V60, I71, V81, V87, L98, I99, Y102, L113, V117, I424, V426, F427, I428,
trisphosphate 5-phosphatase W431, I466, V468, F469, L489, I508, V510, A511, V512, L513, V514, A543, V544, V546, F548, F550, F555, F557, C560,
2 (EC 3.1.3.86) H601, F603, F605, L608, Y610, I619, L631, L637, V646, F657, W688, C689, I692, L693, Y707, C709, I713, V721, F722,
V727, M1201, L1205, L1217, L1228, L1236, V1241, L1250
39 Eukaryotic translation O15372 V36, V39, V45, L67, I78
initiation factor 3 subunit H
40 Neural cell adhesion molecule 2 O15394 L32, F40, C42, A44, W53, L78, I80, A83, C93, A95, V107, A132, V134, C136, I173, I176, Y184, C186, V190, I201, V203,
V205, A220, A222, F230, C232, W244, L266, V268, I271, Y279, C281, A283, A294, L296, I304, L320, C322, W334, F343,
I354, L365, I367, V370, Y378, C380, A382, M393, I418, I420, C422, V424, W434, L460, I462, Y473, C475, A477, Y488,
A493, A512, V514, F516, Y530, V532, L556, I567, V569, A570, A571, L611, I613, A621, V628, L653, L656, V664, I666,
A668
41 Toll-like receptor 3 O15455 A35, C37, I53, L56, L58, L63, L66, F71, Y74, L77, L80, V82, I87, L98, L101, V103, L104, L106, L111, F119, L125, L128,
L130, I135, F143, L149, L152, L154, L164, L170, L173, L176, L178, I183, L186, L191, I193, F194, L199, L202, L204, I209,
C216, F217, L223, L226, L228, V231, L241, C242, L245, I250, L253, L255, L260, F268, L269, L271, L276, L279, L281, L286,
V289, F294, L297, L300, F303, L305, I310, L313, L318, L321, V324, L327, L329, F351, L354, L357, L360, M362, F375, L378,
L381, L384, L386, L396, F401, L404, L409, H410, L412, L414, I419, I422, A426, F427, L430, L433, L436, L438, L440, I443,
L447, W452, L455, I458, I461, L463, L469, L471, F476, V479, L482, L485, L487, V490, L492, V495, F502, L505, L508, L511,
L513, I521, M525, L526, L529, L532, L535, L537, L542, L545, W546, F557, L558, L561, L564, L567, L569, F574, F582, L585,
L588, I591, L593, L595, L598, L601, F606, L612, L615, L617, I622, V625, A633, F634, L640, M642, F647, I654, F657, Y675,
V688
42 Fibroblast growth factor 10 O15520 L82, L90, I92, L111, I113, V123, A125, L132, A133, M134, C150, L152, Y164, M176, V178, A179, L180, A199, F201
43 Leucine-rich repeat transmembrane protein O43155 I75, L100, I121, L129, L132, L135, L138, L140, I159, L161, L163, L164, L166, L185, A193, L203, L206, L209, V211,
FLRT2 L215, L216, F235, I237, L254, L257, L259, L278, L281, L288, L291, F296, L299, L305, I318, L325
44 Kunitz-type protease inhibitor 2 O43291 C84, C133, C179
45 Desert hedgehog protein O43323 A59, V67, A95, M99, C103, V107, L110, A111, V114, L123, V125, W129, L140, H141, A146, L147, I149, Y159, L161,
L162, A163, A166, V174, V182, V184, V186, A188, V194
46 Glutamate receptor ionotropic, delta-2 O43424 V445, V446, F453, V454, F470, V474, L475, L478, A491, L508, V509, A517, I519, I521, L524, V534, V547, L548, L549,
L562, L671, Y679, M708, I712, V732, A738, F739, V740, V745, L746, F758, Y770, I772, A773, L774, F784, I788, M797
47 Tumor necrosis factor ligand superfamily O43557 A96, L98, L112, A132, L133, V135, Y141, I143, V147, L149, I162, H164, L166, L180, V215, V216, V217, L224, F235
member 14
48 Carbonic anhydrase 12 (EC 4.2.1.1) O43570 W43, I58, L60, Y79, L89, V96, L98, M104, I106, L118, L120, H121, W122, H133, A142, L144, H145, I146, H148, A160,
A168, L170, A171, V172, L173, I174, Y183, I186, L190, V193, V202, I207, L210, C230, V234, W236, V238, F239, I245,
L250, L251, L253, A256, L257, M270, V285
49 Alpha-actinin-4 O43707 F56, W59, C60, L64, F78, L82, L84, L87, L88, V112, A115, L116, I119, L126, A131, I134, V135, L143, M145, I146, I149,
I150, A154, I155, I158, L169, C173, V185, F188, W192, A197, F198, A200, L201, I202, L215, V221, L224, A227, F228,
A231, M240, A243, I246, A256, I257, M258, Y260, V261, F264, Y265, A274, A415, F418, A422, L436, I449, I473, L480,
V491, I498, L505, L516, H530, Y533, A537, M544, I563, L577, I587, A594, L605, I619, V626, L637, M679, I719, I743,
M815, I880
50 EGF-like repeat and discoidin I-like domain- O43854 C59, C116, C154, M325, W351, A356, A366, W367, L378, V380, V388, I391, A396, V405, Y408, L410, A411, Y422,
containing protein 3 A453, I456, I458, I467, L469, L473
51 Tolloid-like protein 1 (EC 3.4.24.—) O43897 A148, A149, W157, I162, F178, A181, W185, V191, I203, F205, I226, V238, V239, L242, V245, I246, F248, H250,
H252, V261, I268, F276, I296, M297, H298, I313, A340
52 Peroxisome biogenesis factor 1 O43933 V19, V108, I155
53 Kalirin (EC 2.7.11.1) O60229 L2148
54 Cubilin (460 kDa receptor) O60494 Y952, I962, I970, L1020, F1024, I1037, Y1068, C1074, Y1076, I1086, L1095, L1107, I1109, F1143, F1154, A1156,
C1191, W1193, L1195, A1202, F1203, M1255, F1270, A1272, V1281, L1291, C1306, W1308, V1318, V1368, L1370, F1382
55 Gremlin-1 O60565 C178
56 Toll-like receptor 5 O60602 L72, L75, L94, L97, A114, L121, L124, L144, L147, I157, L169, I175, F177, I182, L190, L314, L317, L338, L341,
L359, V362, I365, A425, V447, L450, L475, V497, L507, L531, L553, I555
57 ATP-binding cassette sub-family C member 9 O60706 M702, I703, V704, C709, L714, L715, A717, I718
58 Voltage-dependent L-type calcium channel O60840 A252, A700, I707, A1015, V1082, A1095, Y1120, A1372, M1389
subunit alpha-1F
59 Matrix metalloproteinase-20 O60882 L45, Y49, L75, L81, L122, I126, V138, A141, V142, A145, L146, A148, W149, V153, L155, A165, I167, I169, F171,
A190, F193, F205, W211, L220, F221, V223, A224, A225, F228, A231, L232, L234, A242, L243, M244, Y245, Y250,
L258, V263, I266, L269
60 Low-density lipoprotein receptor-related O75197 L35, L36, F37, A38, V43, L62, A65, A67, V68, V77, Y78, W79, V82, A86, I87, L113, L122, Y123, W124, I132, V134,
protein 5 M165, Y166, W167, I176, A179, M181, V190, A212, I219, A242, L250, W252, I260, H261, I284, V286, L309, L311,
L312, C321, C323, L344, L345, L346, A347, I355, L357, A375, Y388, W389, A396, I397, L430, Y431, W432, I440,
V442, M473, Y474, W475, I484, A487, L489, L517, W519, I530, L545, I568, L588, M589, C605, L615, C616, F617,
C627, I1274, C1323
61 Core histone macro-H2A.1 O75367 A19, F23, V25, M28, I32, H36, V43, A45, V47, Y48, M49, A50, A51, V52, L53, L56, I60, L61, A64, A67, A68, V76, H80,
I81, L83, V85, L91, V98, A101, L197, L199, I200, I204, L207, A208, F210, A214, I215, I216, I223, L233, F241, V245,
L255, A258, A270, V273, I274, H275, C276, L290, V294, C297, L298, A301, I309, A310, F311, I314, A326, A327, I330,
L331, A333, I334, F338, I346, V349, F351, Y362, M366
62 Filamin-B O75369 F22, C26, L30, I37, L40, L44, L50, I51, L53, L54, V80, V82, A83, L84, F86, L87, I92, I102, I110, L111, L113, V114,
L117, I118, I123, L145, W148, I149, I153, F161, W165, A170, L171, A173, L174, V175, A179, C183, A198, A201, M202,
A205, L209, V211, V214, I215, I220, V230, M231, Y233, L234, F237, A257, A275, V279, A284, V291, V317, H327, V329,
V331, F333, I338, V345, V1043, F1061, I1063, A1068, V1097, Y1099, Y1107, V1109, I1111, I1118, A1125, I1127, V1136,
A1138, V1156, A1161, A1170, V1192, Y1194, Y1202, L1204, M1206, Y1208, V1220, I1231, V1243, F1251, V1253, I1270,
Y1290, V1292, Y1294, H1302, V1304, V1306, V1320, V1331, A1341, F1349, V1351, A1356, A1385, Y1387, Y1395, V1397,
I1399, I1406, V1413, V1424, V1435, V1445, A1450, V1459, V1481, V1493, V1495, Y1497, I1502, V1509, V1511, V1520,
V1532, A1534, F1540, I1542, A1544, A1547, I1556, V1578, Y1580, Y1588, I1590, V1592, Y1594, I1599, I1606, A1608,
A1614, C1617, F1636, V1638, A1643, V1648, V1652, I1674, A1678, Y1684, I1686, V1688, I1695, V1702, A1704, V1755,
V1764, V1784, V1786, H1796, M1798, I1800, I1807, V1824, F1842, I1844, V1878, Y1880, Y1888, I1890, V1892, A1906,
I1908, I1964, F1966, H1974, V1976, I1978, V1994, A2002, A2005, F2023, V2025, V2059, Y2061, Y2069, V2071, F2075,
V2087, I2089, V2133, H2153, V2155, H2165, V2167, V2169, V2185, V2196, F2214, I2216, V2250, Y2252, A2254, Y2260,
V2262, I2264, I2271, V2278, V2280, I2281, A2287, L2290, L2300, I2310, L2312, A2315, I2319, V2323, V2345, H2355,
I2357, V2359, F2361, V2373, V2387, L2394, F2405, I2407, A2412, V2440, Y2442, Y2450, I2452, V2454, Y2456, I2462,
A2469, A2512, V2515, A2525, V2535, C2537, V2571, V2575, V2585, W2587, I2592, V2599
63 Vacuolar protein sorting-associated protein O75436 F42, V48, V52, H65, I68, I70, F72, V73, I76, L101, F111, V114, V126, L128, Y130, F131, L132, V134, V151, M166,
26A L174, I176, F178, Y180, Y185, I191, I195, M207, L209, L211, A231, I246, I248, L250, L252, F268, V270, Y272, L274,
L276, L278, I292
64 Low-density lipoprotein receptor-related O75581 L23, L24, Y25, A26, L31, V34, V47, L50, A53, A55, V56, F58, V59, I65, Y66, W67, V70, A74, I75, V90, V91, L94, L100,
protein 6 C102, L109, Y110, W111, I119, V121, L128, M152, Y153, W154, I163, A166, M168, I177, L189, L196, Y197, W198, A199,
I206, A218, V219, L224, A229, L232, L237, Y238, W239, I247, L248, A249, C250, I271, A273, L296, C297, L298, M299,
C308, C310, L317, L331, L332, L333, A334, L339, I342, L344, A362, Y375, W376, A383, I384, A414, L417, Y418, W419,
I427, V429, L453, M460, Y461, W462, I471, A474, A475, L476, V485, A496, I504, W506, M517, I532, W547, I555, L575,
M576, C592, L602, C603, L604, C614, L634, L635, F636, I642, I645, A664, A666, I676, Y677, I686, A689, V700, V712,
L719, Y720, W721, A722, I729, V731, L755, M762, W764, I773, A776, A777, M778, V787, A793, I798, L805, W807, I815,
A829, L832, I845, W847, I855, A858, I869, V876, V881, C893, L903, C904, A906, L936, L937, F938, I944, L959, V967,
A969, L979, Y980, W981, I982, I989, A992, Y1027, I1028, Y1029, C1032, I1038, V1040, V1051, L1052, A1061, V1062,
M1071, Y1072, F1073, I1083, A1086, A1087, L1088, L1116, F1117, W1118, A1119,
I1126, L1157, W1159, I1160, I1167, L1188, C1207, I1217, C1218, L1219, C1313
65 Oral-facial-digital syndrome 1 protein O75665 M834, H851, V852, A854, A858
66 Protein XRP2 O75695 V57, F62, I64, C67, C70, I72, I74, F75, V81, I83, C86, C89, I91, F92, L93, V96, V100, F102, C105, C108, C110, L112,
A113, C114, F117, V119, C122, L125, V127, L129, C131, I137, I143, F145, F148, W150, Y152, L155, F157, F159, A162,
F167, W171, L189, V195, V199, L207, V221, C236, L237, V238, V239, A248, A250, L253, M257, V270, A277, V280, A285,
V297, A299, L300, F302, A307, V308, C311, A333, F340, A344
67 Gap junction beta-3 protein O75712 L25, A39, W44, F51, C60, C64, W77, V84, I92, L135, L149, C164, V167, C176, M191, C198
68 Isocitrate dehydrogenase [NADP] O75874 V10, V11, M13, M18, I21, I22, W23, L25, I26, L30, I31, V35, L39, L44, I46, A60, A61, A63, I64, V69, V71, C73, A74, I76,
cytoplasmic I99, I102, V107, F108, I112, I113, C114, I117, W124, I128, I129, I130, H133, A134, A179, I189, F192, A193, F197, M199,
A200, L207, L209, F223, I226, F227, F239, I244, M254, A258, F265, I266, W267, A268, C269, V281, A282, Y285, M290, M291,
L295, V296, C297, V303, A305, A307, A308, I330, A331, I333, F334, A335, W336, L340, A344, L352, A353, F355, A356, A358,
L359, V362, I367, F371, M372, L376, A377, A378, F397, M398, L401, L405
69 Tumor necrosis factor ligand superfamily O75888 L219, L225
member 13
70 Dysferlin O75923 L2, V86
71 Multiple PDZ domain protein O75970 M129, A130, F138, L140, I165, V167, A176, I188, L189, A190, I191, L196, A205, V216, L218, V219, I220, A221, I258,
L260, V279, A290, I302, L303, I305, L310, V318, V329, L331, I333, A334, V378, L380, I405, V407, A415, V416, I422,
I428, V431, L436, A444, V455, L457, L459, L703, I728, I730, I738, A739, L745, L751, V754, L759, A767, A774, V779,
I781, V783, V1152, L1154, L1162, I1185, I1187, A1196, L1202, I1208, V1209, V1211, L1216, A1219, A1224, V1235,
F1237, V1239, I1337, L1353, A1365, V1375, F1376, I1377, A1386, L1398, L1399, I1401, L1406, A1414, A1421, V1425,
I1427, I1428, F1429, I1430, A1435, I1630, I1632, I1654, I1656, A1664, A1665, I1677, V1680, L1685, A1693, V1704,
L1706, L1708, I1726, L1728, V1749, A1760, I1772, V1788, V1799, V1803, I1890, I1892, A1901, I1916, A1929, I1940,
M1942, V1944, I1988, L1990, L1997, I2014, V2016, A2025, I2037, V2040, L2045, A2053, L2057, V2064, L2066, V2068
72 Nebulette O76041 A961, F975, I981, V996, L1005
73 Bestrophin-1 O76090 V90, V158, F248
74 Serine/threonine-protein kinase 10 O94804 A53, A62, A64, I82, I84, A86, C88, I93, V94, L106, I108, M109, V118, I121, M122, L125, L129, I134, V136, V137, C138,
(EC 2.7.11.1) M141, L142, A144, L145, L148, H155, L158, A160, V163, L164, M165, L167, I171, L173, F176, V178, A180, A200, A218,
I220, L223, L227, I228, M230, V245, L246, I249, F267, F270, A274, L275, A285, L288, F293, V294, L303, L306, V307
75 Tumor necrosis factor ligand superfamily O95150 A97, L99, L117, M132, L139, I141, Y147, I149, V153, F155, A168, I177, V179, V180, I181, I212, L220, L226, V228,
member 15 V230, V236, F245, F246, A248
76 Interleukin-18 receptor accessory protein O95256 L165, I173, C175, W191, C221, A236, V238, C273, A275, F277, W289, V326, F335, C337, V339, V350, L352
77 Bile salt export pump (ATP- binding cassette O95342 A452, L453, V454, A464, L467, I468
sub-family B member 11)
78 Tumor necrosis factor receptor superfamily O95407 C49, C52, C91, C132
member 6B
79 Apolipoprotein M O95445 F49, I50, A51, A53, A54, I69, V70, L145, L146
80 Gap junction beta-6 protein O95452 I25, A39, W44, F51, C60, C64, H73, W77, V84, A92, I140, F154, C169, I171, C180, M195, C202
81 Follistatin-related protein 3 O95633 V37, W39, A70, V134, C135, C146, L148, L159, C195, C211
82 Interleukin-33 O95760 A124, L126, I134, V159, L160, L161, M183, V184, L186, L194, A196, V203, A216, F217, F218, V219, C227, F230,
C232, I240, L247, A248, F265
83 EGF-containing fibulin-like extracellular O95967 C71, C109, C162, C241, C281
matrix protein 2
84 Cytochrome b5 P00167 I17, L28, I29, L30, V34, L41, L51, A55, L84
85 L-lactate dehydrogenase A chain P00338 I23, V25, V26, V28, A34, C35, A36, I39, L40, M41, A45, L48, A49, L50, V51, L58, L91, V92, I93, I94, L109, V110, V114,
F117, F119, I120, I121, V124, C131, L133, L134, I135, V136, V140, I142, L143, V146, A147, V158, I159, C163, F170,
M174, C185, V189, L190, V198, V200, M204, V206, L218, V230, V234, V256, A257, L259, A260, I263, V273, I277, I283,
V287, F288, L289, V291, C293, L295, L316, A320, L323
86 NADH-cytochrome b5 reductase 3 P00387 L45, L47, F60, F62, L71, L73, I79, L81, V106, L108, V109, I110, M127, L131, F142, L149, F157, V175, M177, I178,
A179, I184, M187, L188, V190, I191, I194, C204, L206, L207, F208, I216, L217, L218, L222, F233, Y237, L239, I258,
L270, V271, L272, M273, C284, L288
87 Cytochrome c oxidase subunit 2 P00403 I83, I97, W106, Y108, V142, L144, I150, M152, I154, H161, W163, A164, V165, L168, A174, F184, M207, I209, V210,
L211
88 Phenylalanine-4-hydroxylase P00439 A34, I35, L37, F39, V51, F55, F79, F80, L83, L91, I94, L98, A104, L109, W120, I125, L128, F131, A132, A165, W187,
V190, F191, L194, A202, C203, Y206, L213, F219, I224, L227, V230, F233, L234, F240, L255, L258, A259, F260, V262,
F263, C265, Y268, I269, I283, C284, L287, L288, H290, V291, L293, F294, F299, A300, F302, I306, A309, L311, A313,
I318, L321, A322, I324, F327, V329, L333, I340, A342, Y343, A345, L347, L348, L354, C357, A373, L385, Y386, Y387,
A389, A395, V399, F402, A403, I406, F410, I421, L424, I432, A434
89 Superoxide dismutase P00441 A5, C7, L9, V15, I18, I19, F21, V30, V32, I36, L39, H44, F46, H47, V48, H49, A61, H64, H72, H81, V82, L85, V88, A90,
[Cu—Zn] (EC 1.15.1.1) A96, V98, V104, I105, L107, I113, I114, L118, V119, V120, H121, A141, A146, C147, I150
90 Coagulation factor VIII P00451 L26, A28, L90, L91, I95, I105, L107, V115, L117, A119, A131, V147, Y155, W157, Y177, L191, I192, A194, L196, V197,
C198, L217, F218, A219, F221, H251, V253, Y256, V272, W274, V276, I277, I288, F295, I307, A315, L319, C329, M339,
A341, V343, V345, I405, A406, A407, Y414, A415, L431, Y442, V445, F447, I467, L472, L480, I482, F484, Y492, I494,
L517, Y530, W532, Y552, L566, I567, L570, L571, I572, C573, L594, F595, F598, Y605, M633, I636, V640, V648, W656,
I658, V670, F677, L689, V697, M699, M701, L709, C711, M721, A723, L725, I1719, A1720, A1721, V1752, V1753, F1754,
H1774, L1775, L1777, L1778, I1782, A1784, I1790, V1792, F1794, Y1802, F1804, V1826, W1836,
V1838, M1842, C1851, A1853, Y1856, H1867, L1870, I1871, L1874, L1875, V1876, C1877, V1892, F1895, A1896,
L1897, F1899, F1902, F1937, H1938, A1939, I1940, L1948, L1951, M1953, A1954, I1959, W1961, Y1962, L1963,
L1964, H1973, I1975, F1977, F1982, L1997, V2005, V2017, C2019, M2029, F2033, V2035, M2046, A2066, A2070,
A2080, W2081, I2099, I2100, H2101, A2108, I2117, F2120, I2122, Y2124, Y2134, F2145, I2163, I2164, A2165,
L2181, L2185, M2186, C2188, C2193, M2199, I2209, A2220, W2222, A2227, A2237, W2238, L2249, V2251, F2253,
V2259, V2262, V2267, M2274, V2276, F2279, I2281, F2302, L2316, L2325, I2327, I2336, A2337, L2338, M2340,
V2342, A2347
91 Coagulation factor XIII A chain P00488 L46, H65, Y70, L75, I76, V77, F83, V85, I87, F89, F100, V102, Y104, V105, I106, V120, A133, V136, V143, L145, I147,
V155, F158, Y161, V162, A163, Y182, I183, L184, F185, V194, L196, Y205, V206, I213, F214, W226, I235, C239,
V242, M243, L250, V259, M266, V275, L276, A292, W293, I299, Y303, V310, C315, W316, V317, F318, A319, V321, F322,
L326, C328, L329, I331, A333, V336, Y339, A342, L349, I353, L355, Y373, H374, C375, W376, A379, M381, F390,
A395, V396, C410, A413, A417, I418, H420, H422, A429, V432, F433, A434, V436, L440, I441, Y442, I461, I465, V466,
Y482, L493, A498, V519, M521, F523, F534, L536, I538, F540, I550, A552, Y553, L554, A556, I558, Y561, V576,
L578, I590, Y595, L605, H606, F607, F608, V609, A611, I613, V619, L620, L628, V642, M647, V649, V651, F653,
L661, V664, V666, L668, I684, C696, L706, I707, A708, M710, L715, H717, V718, V724
92 Hypoxanthine-guanine P00492 V35, I37, I42, L49, A50, V53, M57, I62, V63, A64, L65, C66, L68, F74, F75, L78, L79, I82, I93, I100, L125, V130, L131,
phosphoribosyltransferase I132, V133, I137, M143, L146, L149, V150, V160, A161, L163, L164, F181, I183, V188, V189, Y191, A192, F199,
L202, V205, C206, V207
93 Tyrosine-protein kinase P00519 L88, C100, A102, V111, W127, A137, L141, F149, L150, V151, I163, L165, A179, L198, V199, H202, L213, A217, I242,
ABLI (EC 2.7.10.2) V268, V270, F283, L284, A287, V289, M290, I293, L298, L301, V304, C305, Y312, I313, I314, L323, L327, V335,
V339, L340, M343, A344, I347, A350, M351, L354, I360, H361, L364, A365, A366, C369, V371, V377, V379, F382,
L384, F401, A407, L411, V422, W423, F425, V427, L428, L429, Y440, V448, L452, M458, C464, M472, C475, W476,
F486, I489, F493
94 Epidermal growth factor P00533 L41, F55, C58, V61, L65, I67, V70, L79, I82, V85, Y88, V89, L90, I91, A92, V96, I99, L101, L104, I106, I107, A118,
receptor (EC 2.7.10.1) L119, A120, V121, L132, L135, M137, L140, I143, A147, V148, F150, L156, V159, I167, V168, C199, W200, C223, C236,
A237, A238, C240, C260, V300, V301, C326, C337, I340, F345, I351, I356, F359, C362, I365, L369, I371, V374, A375,
L392, L395, V398, I401, L405, L406, I407, L417, A419, F420, L423, I426, L438, A439, V440, V441, L443, I445, L448,
L450, L453, I456, V461, I463, L469, C470, Y471, A472, I475, L480, C499, C510, C515, W516, C571, C624
95 Adenylate kinase P00568 L5, I10, F12, V13, V14, C25, I28, I60, L73, L76, M80, F90, L91, I92, Y95, F105, I109, L114, L115, L116, V118, M125,
isoenzyme 1 I146, V160, Y164, V173, V186
96 Prothrombin (EC 3.4.21.5) P00734 Y87, C90, A93, L100, C103, A109, Y116, C129, C157, W168, C169, Y170, C181, I183, A242, C262, V272, W273, C274,
Y285, C286, V295, F324, F329, C336, L355, I364, V365, A370, M374, W377, V379, M380, L381, F382, L390, C391,
A393, L395, I396, W400, V401, L402, A404, A405, H406, C407, L408, L409, L422, L423, V424, I426, L444, H450, I463,
A464, L465, M466, L468, V472, I478, H479, V481, C482, L483, A489, L492, L493, A495, V501, W504, L507, L523,
V525, V526, L528, I530, V531, C536, I544, M548, F549, C550, A551, A563, C564, F572, V573, M574, W582, M585,
I587, V588, C594, Y600, F602, Y603, H605, V606, F607, L609, W612, I613, V616, I617
97 Coagulation factor IX (EC P00740 C128, V132, V227, A233, V242, V243, L244, I256, V257, I262, V263, A265, A266, I275, V277, V278, A279, I316,
3.4.21.22) A317, L318, L319, L321, V331, V353, W356, L369, V374, C382, F395, C396, A397, H415, V416, L425, I428, I443,
Y444, V447, Y450, V451, I454
98 Coagulation factor X (EC P00742 C121, C136, I235, V236, C241, C246, A250, L251, L252, I253, C261, I265, L266, I271, L272, A274, A275, C277,
3.4.21.6) V286, V288, V302, I309, H311, I323, A324, V325, L326, L328, V338, A341, C342, A349, L353, G359, V361, F364,
L377, M379, L380, V382, C390, L392, M402, C404, A405, H423, V424, F432, V433, I436, A444, I451, Y452, V455,
F458, W461, I462
99 Complement factor D (EC P00746 I26, L27, M40, A41, V43, C51, V54, L55, V61, L62, A64, C67, V78, L80, L115, L116, L117, L118, L120, L126, L133,
3.4.21.46) C148, V150, A151, W153, V169, L171, C179, I189, L193, C195, A196, C204, L212, L218, V221, V222, C229, Y238,
V241, I248
100 Plasminogen (EC 3.4.21.7) P00747 A31, C49, C53, C61, A63, F64, C73, M76, Y111, W127, C152, W163, C164, Y165, C176, I178, M186, Y193, W209,
[Cleaved into: Plasmin H217, Y219, C234, W244, C245, F246, C257, I259, Y283, C296, W299, L319, C324, W334, C335, H336, C347, I349,
heavy chain A; Activation Y385, C398, W401, H407, H409, L421, C426, W436, C437, F438, C449, L451, Y489, C502, W505, H513, C531, W542,
peptide; Angiostatin; C543, Y544, C555, V557, C577, V581, W594, V596, L598, C607, L611, V617, L618, A620, C623, Y633, V635, I636,
Plasmin heavy chain A, L637, V654, I666, A667, L668, L669, L671, V681, I682, A684, C685, C699, I701, W704, L716, A719, L721, V723,
short form; Plasmin light C729, L735, L744, C745, A746, H748, L764, V765, C766, Y772, L774, V777, A785, V792, Y793, V794, V796, F799,
chain B] V800, I803
101 Coagulation factor XII (EC P00748 C135, V158, C161, C163, C209, A388, A389, A398, L401, L408, A410, A411, L414, V425, L427, L462, A463, L464,
3.4.21.38) L465, L467, V482, C500, A503, W505, C532, C548, A549, L567, V568, C569, L580, I583, V598, V602, I609
102 Complement factor B (EC P00751 L58, A96, C103, Y121, I127, C145, C158, C165, V177, V187, C205, M223, V230, A231, F234, L235, I242, M269, I271,
3.4.21.47) Y272, L273, V274, L275, I281, F286, A289, C292, L293, I297, V300, Y309, L311, V312, Y314, A315, V322, V324,
V335, L339, I342, A358, L359, V362, V383, I384, I385, L386, M387, L391, V401, I405, L409, I411, Y426, V427, F428,
V430, I439, A443, H451, F453, V455, M458, L461, V464, F465, M468, V481, W495, A497, I499, V501, C511, M512,
A514, V515, V516, F520, V521, L522, A524, A525, C527, F528, V530, V539, V541, I569, V577, A578, L579, I580,
L582, C596, C599, A606, L607, L622, I628, A630, L631, F632, V633, V645, I647, C656, A660, A663, V669, V675, V676,
F680, L681, C682, C695, L703, I704, V705, F711, I712, V714, V716, V721, A738, F741, H742, I743, L745, V748,
L752, L756, L761, L764
103 Renin (EC 3.4.23.15) P00797 I90, I92, F99, V101, V102, F103, V110, W111, V112, C117, A123, C124, F130, V154, I162, I163, V165, V170, M173,
F174, M180, V193, V194, M196, F198, I209, F210, I213, V218, V223, F224, F226, Y227, Y228, I242, I262, V266,
W267, I269, M271, V274, L288, A289, V291, I298, I305, L308, M309, V322, V323, C325, L331, I334, F336, L338, Y343,
L345, Y350, F352, C362, L364, A365, I366, A380, L381, A383, F385, I386, Y390, F393, I400, F402, A403
104 Carbonic anhydrase 2 (EC P00918 W16, V31, I33, Y51, I59, A65, F66, V68, F70, A77, V78, L79, Y88, L90, F93, H94, F95, H96, W97, H107, A115, A116,
4.2.1.1) L118, H119, L120, V121, H122, W123, A133, V134, L140, A141, V142, L143, I145, F146, L147, V149, L156, V159,
V160, V162, L163, I166, F175, F178, L183, L184, L188, Y190, W191, Y193, L197, L202, L203, C205, V206, W208,
I209, V210, L211, I215, V217, V222, F225, L228, F230, M240, L250, I255, A257
105 Argininosuccinate synthase P00966 V7, V8, L9, C19, I20, L21, W23, L24, V31, I32, A33, Y34, L35, A51, V64, F68, V69, F72, I73, I77, L89, L93, A94, C97,
(EC 6.3.4.5) A99, I105, A106, Y113, C132, A143, F150, Y163, A164, L185, M186, H187, Y190, L195, L206, L223, I225, F227, V235,
V238, L250, F251, L254, V257, A258, H261, V263, V269, I281, A286, I289, L290, A293, H294, I297, F317, A318, V321,
Y322, C331, I338, V345, V349, V351, V353
106 Serine protease inhibitor P00995 V46, C47, L60, C61, I71, I73
Kazal-type 1
107 Antithrombin-III P01008 M49, A75, V80, L83, A86, F90, A91, F94, Y95, L98, I108, F109, L110, L113, I115, A118, F119, A120, M121, A126, C127,
L131, L134, M135, V137, F138, F140, I143, I151, H152, F153, F154, F155, A156, L158, L162, A166, A175, L178, F179,
V197, A200, F207, I218, V222, I230, I234, A238, L242, V244, L245, V246, L247, V248, I251, F253, W257, F261,
F271, A281, M283, M284, V301, L302, L304, F306, I311, M313, V314, L315, I316, L317, V327, L331, L343, L348,
V349, V350, M352, I357, L363, L367, L372, L375, L383, I386, A388, L394, V396, A399, H401, A403, L405, V407,
A414, A415, A416, A419, V420, V421, I422, A423, F434, A436, F440, L441, V442, F443, I444, V447, I453, F454,
M455, V458, A459
108 Alpha-1-antitrypsin P01009 F47, I50, L54, F57, A58, F59, L61, Y62, L65, I74, F75, F76, V79, I81, A82, A84, F85, A86, M87, L88, I100, L101, L104,
F106, I111, I116, F120, L123, L124, L127, L134, L142, F143, L144, F154, V158, L161, Y162, V169, F171, A177, I181,
V185, I193, V197, V205, F206, A207, L208, V209, I212, F213, F214, W218, F222, V224, F232, V234, V242, M244, M245,
F251, I253, L259, V263, L264, M266, Y268, A272, A274, I275, F276, F277, L278, L284, L287, L291, I295, F299,
L300, A308, L310, H311, L312, I317, L323, L327, L330, I332, V335, A340, L342, V345, L351, L353, A356, V357,
H358, A360, V361, L362, I364, A371, A372, A374, M375, F376, L377, A379, I380, V388, F390, F394, V395, F396,
L397, M398, L407, F408, M409, V412, V413
109 Angiotensinogen P01019 V44, A103, V106, L109, A110, L113, F115, I117, Y118, V133, L134, A138, V139, F140, L143, A144, L146, L158, L16
2, V164, L175, V180, L181, A183, L184, A186, V187, L191, V192, L203, L205, V208, V209, V211, F212, L217, L219,
F223, L227, Y230, F241, A247, M255, V258, L276, A277, F278, Y281, V282, F284, M288, F291, F300, V310, L313,
V331, V334, A340, C341, L342, L343, L344, I345, V356, F361, I377, L379, M381, L384, L392, L395, L396, I404, L405,
L409, L411, L414, V424, I428, F430, L432, L456, F460, L461, A463, V464, A469, A471, L472, H473, F474, L475, V478
110 Complement C3 P01024 M25, I28, I29, L34, M42, L44, A46, H47, V55, V57, V59, L76, V86, F88, I90, V106, V108, A110, F112, V117, V121, L122,
V123, Y129, I138, Y139, V145, Y147, I149, F150, V152, V163, V165, I167, V188, L189, W204, I206, A208, Y210,
F222, V224, F232, Y243, I245, L251, V253, I255, A257, V265, A269, V271, F273, I275, L284, I293, V300, L302, L319,
L324, V326, A328, V330, I346, I348, I355, F364, M368, F370, L372, V374, V376, A384, V387, V389, L400, A407,
L409, I422, V424, A443, Y446, Y455, L456, L465, V473, F475, I487, Y490, L493, I494, I521, I526, F529, L531, V532,
A533, Y534, Y535, L537, V546, V547, A548, V555, I585, A591, V593, V596, A597, V602, I616, W617, V620, V638, F639,
A642, L644, F646, C693, C694, M698, M703, V723, F724, C727, C728, I731, W802, A806, V825, F829, L833, V839,
V840, V845, I847, A849, L851, L860, V862, V864, L866, A871, C873, A876, I888, V896, Y898, V899, I900, V901, V910,
V912, A914, A915, V916, V925, L929, V931, L947, I962, V971, I980, L982, V987, M990, A994, V995, A997, L1000,
L1003, C1010, M1015, I1016, M1018, V1022, I1023, A1024, V1025, Y1027, L1028, A1045, I1049, L1057, A1058,
F1059, A1065, F1066, A1067, A1068, F1069, A1073, L1078, A1080, Y1081, V1082, V1083, V1085, F1086, L1088,
A1089, V1090, L1100, C1101, A1103, V1104, L1107, V1117, F1118, V1124, H1126, M1129, M1141, A1142, A1145,
F1146, V1147, L1148, I1149, L1151, A1154, C1158, V1162, L1165, A1172, L1176, Y1180, L1183, Y1187, V1189,
A1190, I1191, A1192, A1195, L1196, A1197, L1202, F1210, W1220, L1227, Y1228, V1230, A1232, Y1235, A1236,
L1237, L1238, A1239, L1240, L1241, V1249, V1252, V1253, L1256, Y1266, A1271, F1273, M1274, V1275, F1276,
A1278, L1279, A1280, Y1282, L1292, L1294, V1296, L1298, I1311, F1330, V1332, A1334, L1342, V1344, Y1348,
A1350, F1361, L1386, I1388, C1389, I1402, L1403, I1405, M1407, M1408, F1411, A1412, L1418, L1421, I1429,
L1444, I1446, Y1447, V1451, A1460, F1461, V1463, L1471, A1476, V1477, V1479, A1481, Y1482, Y1483, C1489,
Y1493, C1518, A1536, Y1543, V1544, Y1545, L1549, F1558, Y1561, M1563, I1565, F1584, C1590, Y1602, L1603,
M1604, W1605, Y1620, L1649, F1652
111 Complement C5 P01031 V24, I25, A27, F31, V33, A35, I39, V40, I41, F50, A52, I54, I56, V71, L73, L85, I87, V102, V106, M117, L126, Y135,
V141, V143, V145, Y146, L148, L161, F163, I183, I190, W199, I201, A203, Y205, F217, V219, I238, F246, I248, I250,
A252, V260, A263, V265, I267, F269, I271, M283, L292, F301, V307, L310, L323, I325, V327, V329, Y347, L363, I371,
V373, V375, V388, L390, A418, V428, L431, F433, V435, A448, A454, Y457, L465, I484, V486, Y499, L502, I503, I526,
M534, L540, L541, V542, Y543, Y544, L554, V555, L561, I563, V573, V588, L590, M592, V600, A601, L602, A603,
A604, V605, A608, V609, L620, A643, V645, F646, A649, L651, F653, I683, A687, V695, C698, C699, C711, C724,
I725, A727, F728, C731, C732, V734, A735, V780, W797, I799, V802, I804, C810, V819, V823, V833, I839, L841, V845,
Y846, C856, V888, V896, V900, L901, I910, F912, L914, L927, L944, V968, L977, V979, V984, I987, L988, A1008,
A1010, L1012, V1015, F1019, Y1020, V1021, Y1024, L1025, L1049, V1068, W1077, L1078, A1080, F1081, A1082, L1083,
V1089, L1104, L1107, I1127, L1142, Y1143, A1146, F1147, V1149, I1150, I1152, A1155, C1159, I1164, A1167,
L1168, A1171, L1175, F1186, L1188, A1189, I1190, A1192, Y1193, A1194, F1205, I1208, F1227, W1228, A1245,
V1248, A1252, Y1253, A1254, L1255, L1256, L1259, V1267, V1270, I1271, W1273, L1274, F1284, I1291, A1293, I1294,
L1297, L1303, L1309, M1311, I1313, V1315, M1328, F1333, V1340, L1346, V1348, A1357, V1359, V1361, V1365,
I1402, A1404, A1406, Y1408, H1421, A1422, V1423, M1424, I1426, L1439, L1442, F1450, V1460, L1462, I1467,
V1475, F1477, I1479, A1491, F1493, V1495, Y1498, H1499, C1505, V1519, A1545, A1552, I1557, Y1559, A1560,
Y1561, V1563, Y1577, A1579, L1581, A1590, I1598, F1600, A1609, Y1617, L1618, I1619, M1620, A1624, Y1637,
I1645, C1657, F1660, L1664, F1667
112 Complement C5a P01032 C22, C47, A50, C55
anaphylatoxin
113 Cystatin-C P01034 V49, A52, A56, L90, V92, L94, G95, C109, C123, F125, I127
114 GTPase NRas P01111 Y4, L6, V7, V8, V9, A11, V14, L19, L23, V29, V44, I46, C51, L52, L53, I55, L56, A59, M67, M72, F78, L79, C80, V81,
F82, A83, I84, F90, I93, L95, Y96, I100, V103, V109, M111, V112, L113, V114, L120, V125, A130, A134, A146, V152,
A155, F156, L159, V160, I163, M168
115 Platelet-derived growth P01127 V127, V153, V170, L172
factor subunit B
116 Low-density lipoprotein P01130 I40, V45, C52, I83, C95, C116, I122, C134, C155, I161, A166, C173, C204, C222, C318, C338, C352, C377, Y400, L401,
receptor F402, F403, V409, M412, L414, I423, A431, L432, V436, I441, W443, I451, A480, V481, I488, Y489, W490, V498,
V500, A501, M531, Y532, W533, I542, L547, V556, L575, W577, V578, I585, L605, L611, A612, V618, F619, W620,
A627, I628, A631, A643, L646, C667, C677, C681, L682, C698
117 Transforming growth factor P01137 L258, C293, C294, V295, F302, C326, L340, A341, L364, I366, C387, C389
beta-1
118 Beta-nerve growth factor P01138 C136, V157, V159, V163, C189, A210, A218, A219, I223, I225
119 Vasopressin-neurophysin 2- P01185 C44, C52, I57, C58, C59, C65, A72, C75, C92, C98, A99, A100, C104, C105, C110
copeptin
120 Somatotropin P01241 F36, A39, A43, L46, L49, A50, Y54, F70, C79, I84, L99, L101, L102, I104, L106, L107, L108, I109, W112, V116, L119,
F123, A131, V136, L140, L143, I147, L150, Y186, L189, F192, M196, V199, F202, L203, V206
121 Insulin [Cleaved into: P01308 L35, A38, L39, I91, C95, L105, C109
Insulin B chain; Insulin A
chain]
122 Insulin-like growth factor II P01344 L37, L41, F52, I66, C70, C75, L80, Y83, C84, A85
123 Lymphotoxin-alpha P01374 A65, L67, I68, L94, L99, V101, Y107, V109, V113, F115, L131, H133, V135, L181, V198, F200, A202
124 Tumor necrosis factor P01375 A90, V92, A94, A98, L105, V117, L124, V125, V126, L131, Y132, L133, I134, V138, F140, C145, V150, L152, H154,
I156, A160, L202, L208, A210, V226, F228, I230
125 Interferon gamma P01579 Y6, I7, F10, C13, I14, A31, L34, A40, F52, L56, I67, M68, I72, V73, Y76, F77, L79, F80, I89, V93, I96, M100, F104, F105,
F115, A132, I133, L136, M140, L158
126 Interleukin-1 alpha P01583 I135, L136, A163, F166, A170, Y171, A178, V182, I183, Y192, I214, L221, F223, F234, I244, A245, V252, L254, F264
127 Interleukin-1 beta P01584 C124, L126, L134, V135, L142, A144, V156, F158, M160, V163, V174, A175, L176, L178, L185, C187, M211, F215,
V216, F217, L226, F228, I238, F262
128 Erythropoietin P01588 L39, A46, A49, C56, C60, L62, V68, A87, V90, L94, L97, A100, L118, V122, A125, L129, L132, L136, A141, A145,
A162, L168, F169, F175, L176, L180, Y183
129 Interleukin-2 receptor P01589 A38, L47, C67, C80, C125, V143, V148, Y150, C168
subunit alpha
130 T-cell surface glycoprotein P01730 L39, C41, A43, F51, W53, I61, L62, L69, L76, A80, W87, F92, L94, I95, I96, L99, Y107, C109, V111, V118, L120, L121,
CD4 V122, F123, L134, L139, L141, L143, V153, C155, L169, V171, L174, W182, C184, V186, I199, V201, V219, F221,
F223, L238, F254, V261, M274, L282, L284, A287, A292, L297, L299, L308, V312, L314, V315, V316, M317, L326,
C328, V330, L340, L342, V358, W368, C370, L372
131 Ig epsilon chain C region P01854 I131, L133, C135, V137, W149, L178, W185, Y191, C193, V195, I237, C239, V241, V251, V280, L284, Y297, C299,
V301, L310, V326, L343, C345, I347, F350, I355, V357, W359, V386, L390, V392, F403, C405, A407, V408, H409,
A412, V418, V424
132 HLA class I P01889 M29, Y31, Y33, F46, V52, F57, V58, F60, A73, W75, I76, Y83, Y91, A95, L102, L105, L119, M122, C125, V127, Y140,
histocompatibility antigen, Y142, Y147, I148, L150, L154, W157, A163, A164, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223,
B-7 alpha chain L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, V285, H287
133 HLA class II P01903 F47, M48, F49, F57, V59, A77, A81, A84, A86, I88, L130, I131, C132, I134, F137, W146, F173, L176, L179, Y186,
histocompatibility antigen, C188, V190, H192
DR alpha chain
134 HLA class II P01906 H50, F58, V60, I78, A85, M89, L131, I132, C133, V135, I138, W147, I174, L177, L180, Y187, C189, V191, H193
histocompatibility antigen,
DQ alpha 2 chain
135 HLA class II P01909 H50, F58, V60, A84, I88, L130, C132, V134, I137, W146, I173, L176, L179, Y186, C188, V190, H192
histocompatibility antigen,
DQ alpha 1 chain
136 HLA class II P01911 F36, L37, F46, F47, V53, F55, L56, Y59, V67, F69, F76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145,
histocompatibility antigen, C146, V148, F151, W160, M171, L190, V199, Y200, C202, V204
DRB1-15 beta chain
137 HLA class II P01912 F36, L37, F46, F47, V53, Y55, L56, Y59, V67, F69, F76, W90, L97, C108, V120, V128, L138, L143, L144, V145, C146,
histocompatibility antigen, V148, F151, W160, V171, L190, V199, Y200, C202, V204
DRB1-3 chain
138 HLA class II P01920 F39, V40, F49, V56, Y58, V59, Y62, A70, F72, Y79, W93, L100, C111, L123, V131, L141, L146, L147, V148, C149,
histocompatibility antigen, V151, F154, W163, V174, L193, V202, Y203, C205, V207
DQ beta 1 chain
139 Collagen alpha-1(I) chain P02452 C63
(Alpha-1 type I collagen)
140 Collagen alpha-1(II) chain P02458 C57
(Alpha-1 type II collagen)
[Cleaved into: Collagen
alpha-1(II) chain;
Chondrocalcin]
141 Collagen alpha-1 (III) chain P02461 C55, C1262, L1265, V1279, I1290, C1294, I1303, V1310, V1326, F1328, A1364, I1368, Y1370, A1377, L1390,
L1392, F1400, C1417, F1429, Y1431, L1439, I1441, I1444, A1445, V1458, V1463, F1465
142 Collagen alpha-1 (IV) chain P02462 V1448, L1474, Y1475, L1487, Y1521, W1522, L1523, I1545, C1548, A1549, V1550, C1551, A1553, F1583, H1586,
[Cleaved into: Arresten] C1604, F1613, I1614, C1616, C1622, C1662, V1664, C1665, M1666
143 Alpha-crystallin A chain P02489 L75, V77, V94, I96, V124, L129, L139, F141
144 Apolipoprotein A-I P02647 V35, L38, A39, Y42, L46, Y53, F57, L106, V117, L138, Y139, L198
145 Apolipoprotein E P02649 W44, A47, F51, L55, V58, V65, L69, L70, V74, L78, M86, L89, L96, L100, A109, L111, L115, A117, A118, L122, M126,
V129, C130, L133, Y136, L144, L151, V153, L155, A156, L159, L162, L166, L173, L177, Y180, A194, L247, L270, V298
146 Fibrinogen alpha chain P02671 I675, Y692, W708, L714, L724, V726, L728, A738, Y740, V744, Y751, L753, A762, A765, H780, F785, C799, A800,
[Cleaved into: W807, Y809, A815, L817, V841, W843, L853, V856, M858
Fibrinopeptide A;
Fibrinogen alpha chain]
147 Fibrinogen beta chain P02675 C241, I244, M254, Y255, I257, V268, C270, W279, I282, F292, Y299, C316, Y322, W323, I329, L340, L341, I342,
[Cleaved into: M344, A354, H355, Y356, F359, V361, Y368, V372, A379, A382, L383, A387, H400, F405, C424, W432, W433, Y434,
Fibrinopeptide B; A439, A440, Y447, Y452, V465, V466, W467, M477, M480, M482
Fibrinogen beta chain]
148 Fibrinogen gamma chain P02679 C179, I182, Y193, I195, V206, C208, V219, F220, Y237, W253, I259, I262, Y270, A271, L272, V274, L276, A286, Y288,
A289, F291, V293, Y300, L302, F307, A312, A315, F316, F321, H333, F338, F348, C352, A353, W360, W361, M362,
H366, A367, H369, L370, Y375, Y380, Y389, I393, I394, W395, M405, M410, I412, I413, L418, H427, A431
149 Acetylcholine receptor P02708 V153, L154, A167, V177, V201, I203
subunit alpha
150 Band 3 anion transport P02730 M435, C479
protein
151 Protein AMBP [Cleaved P02760 C287, A304, C333
into: Alpha-1-microglobulin
152 Transthyretin P02766 L32, V34, V36, A45, V48, V50, V52, L75, L78, F84, I88, Y89, V91, I93, Y98, W99, A111, A117, I127, A128, A129, L130,
L131
153 Serum albumin P02768 V31, A32, F43, A45, L46, V47, L48, I49, A50, F51, A52, Y54, L55, C58, H63, L66, V70, A74, C77, C86, L93, L98, A102,
M111, C114, F126, C148, F151, L163, A167, F173, A175, L178, F181, A182, A188, F189, C192, L202, L209, A215,
C224, A225, F235, A239, A241, F247, A250, A253, V255, L258, V259, V265, C270, L274, L275, C277, A285, I295, L299,
C302, V317, F333, V334, V339, Y343, F354, A359, V367, L369, L370, L371, L373, Y377, L381, C384, Y394, V397, F401,
V405, C416, F427, L431, L432, V439, V442, L447, V448, V450, L454, V457, C461, A473, V480, L481, L484, V486,
H488, V497, C500, F512, F531, A535, I537, A552, L553, V554, L556, V557, A563, L568, V571, F575, F578, V579,
C582, F592, L607, L609
154 Ferritin light chain P02792 V13, A15, V17, L20, V21, Y24, A27, Y31, L34, Y37, F38, V48, F51, F52, L55, A56, Y63, L66, L67, M69, W90, A96,
M97, A99, A100, M101, L107, L111, L112, L114, L126, L130, F134, M145, L149, L152, F167
155 Capsid protein/genotype D P03147 F9, L15, L19, F23, F24, A36, Y38, A54, L55, C61, W71, W102, F103, L108, F110, V120, F122, W125, A131, Y132,
subtype adw (isolate United A137, I139, L140
Kingdom/adyw/1979)
(HBV-D)
156 Estrogen receptor P03372 C185, V187, C188, V199, C202, C205, F209, C227, I229, C237, A239, C240, L242, C245, M250, A307, M315, L319,
A322, M342, L345, L349, L354, M357, I358, W360, A361, V364, F367, V376, L378, L379, A382, W383, I389, L391,
V392, L402, A405, L408, L410, V418, F425, F435, F445, V446, C447, L448, I452, L453, L454, V458, H474, I475,
V478, I482, L486, M490, L507, I510, I514, M517, M522, M528, L540, L544
157 Fusion glycoprotein F0/strain A2 P03420 F32, C37, A39, V40, A47, L48, V56, I57, I59, V76, I79, L83, A89, V90, L93, L158, V164, L171, V187, L188, L195, I199,
L203, C212, I214, V220, F223, L230, I233, F237, V247, M251, L252, L257, L260, I261, M264, I266, M274, I280, V281,
I288, S290, I291, L297, A298, Y299, V300, V301, L303, Y306, C313, C322, I332, C333, L334, Y342, C343, V349, F351,
F352, V365, F366, C367, I379, L381, C382, C393, I395, I407, L410, A412, I413, V414, C416, C422, A424, V442, M447,
V450, V459, I475, Y478, A490, V495
158 Hemagglutinin [Cleaved P03441 A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, F94, C97,
into: Hemagglutinin HA1 Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180, V182,
chain; Hemagglutinin HA2 H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, I242, L243, I245, L251, I252, A253, F258, I274, C281,
chain]/strain I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
A/Bangkok/1/1979 H3N2 I478, I481, A495
159 Hemagglutinin [Cleaved P03446 I20, C21, I22, V33, V43, L58, C59, L69, C72, L74, I78, L79, Y95, I96, V97, L118, F122, C150, M163, L166, I188, V189,
into: Hemagglutinin HA1 F190, W192, I194, Y207, V216, M242, Y244, L249, V255, I257, L263, I264, A265, C294, L327, A347, Y364, A386, L460,
chain; Hemagglutinin HA2 L468, H484, C486, C490
chain]/strain
A/Duck/Alberta/60/1976
H12N5
160 Hemagglutinin [Cleaved P03448 A8, I19, I21, V42, L48, L49, F57, C58, L66, L68, C71, I73, W76, I77, L78, C83, L86, W92, Y94, I95, V96, Y107, L117,
into: Hemagglutinin HA1 L120, I121, V127, F133, C151, Y153, L163, L164, W165, I166, I177, I189, L190, Y191, F192, W193, V195, H196, H197,
chain; Hemagglutinin HA2 Y208, V215, M217, I243, Y245, I249, L250, L256, V258, L264, I265, A266, Y269, A270, F271, F273, A281, C292, C296,
chain]/strain V302, L303, I317, V324, L329, L331, A332, A349, M361, Y366, A388, V389, A440, L452, V459, L462, V466, L470,
A/Shearwater/Australia/1972 C481, H486, C488, C492, M493
H6N5
161 Hemagglutinin [Cleaved P03456 I19, C20, I21, V32, V42, Y57, C58, L68, C71, I73, I77, Y78, Y94, I95, V96, L117, F121, C149, I162, L165, I188, I189,
into: Hemagglutinin HA1 F190, L191, W192, I194, Y207, V216, M242, Y244, L249, L255, I257, L263, I264, A265, C295, A348, Y365, A387, L461,
chain; Hemagglutinin HA2 L469, H485, C487, C491, A509
chain]/strain
A/Turkey/Ontario/6118/1968
H8N4
162 Hemagglutinin [Cleaved P03457 L10, I21, C22, I23, V34, V44, L51, L59, C60, L68, L70, C73, I75, I79, Y80, Y96, I97, V98, L119, F123, C151, M159, L162,
into: Hemagglutinin HA1 A174, I184, L185, F186, M187, W188, I190, Y203, V212, I238, Y240, L245, L251, I253, L259, I260, A261, C290,
chain; Hemagglutinin HA2 H304, L323, A343, Y360, A382, L456, L464, H480, C482, C486
chain]/strain
A/Turkey/Wisconsin/1/1966
H9N2
163 Neuraminidase (EC P03471 W87, I94, F97, I106, I114, V116, Y121, V122, C124, F132, A133, L134, L140, L158, L159, C175, A177, C183, L190,
3.2.1.18)/strain V192, C193, V194, A201, A203, F205, Y207, L223, C230, V231, C232, V239, V240, M241, I254, L255, F256, I257,
A/Memphis/1/1971 H3N2 V275, C278, C280, Y281, Y284, V287, C289, I290, C291, V302, V303, I305, Y316, V317, C318, L321, V322, V349, W352,
A353, F354, V360, W361, M362, Y374, F377, V379, I397, V398, I409, F410, I418, C421, F422, Y423, V424, L426, V436,
W438, I443, V444, V445, F446, I464
164 Neuraminidase (EC P03472 L88, I95, A106, V107, V115, V117, Y122, V123, C125, F132, Y133, A134, L135, L159, I160, W162, C177, I178, C185,
3.2.1.18)/strain M192, I194, C195, I196, A203, A205, V206, I207, Y209, A221, L225, C232, V233, C234, C239, V241, V242, F243, I256,
A/Tern/Australia/G70C/1975 Y257, Y258, F259, H276, I277, C280, C282, Y283, I289, C291, C293, V304, I305, I307, Y318, I319, C320, V323, L324,
H11N9 V350, F353, Y355, W362, L363, I369, Y375, M377, L378, V380, A383, I397, V398, F410, M411, Y420, A422, C423,
F424, Y425, V426, L428, V438, I445, V446, M448, C449, A464
165 Neuraminidase (EC P03474 F92, I114, I115, F119, V120, A121, F130, L132, L156, V159, A175, A176, A181, C182, I191, V193, A200, L201, V202,
3.2.1.18)/strain B/Lee/1940 I204, I221, L222, I232, C236, Y237, L238, M239, I240, A245, F253, L254, I256, I265, H273, C277, I287, C289, A290,
C291, A298, F302, V303, L305, I314, L323, I333, H354, W364, M377, L379, M400, V401, F411, C424, I425, I427, M429,
V430, H431, H439, A441, A442, A444, I445, Y446, L448, L454, L455
166 Neuraminidase (EC P03476 F94, I106, V116, Y121, V122, C124, F132, A133, L134, L158, F161, C176, C184, M191, V193, C194, M195, A202, A204,
3.2.1.18)/strain I206, Y208, L224, C231, C233, V240, A241, V242, V255, Y256, W257, I258, L277, C280, C282, I286, V288, C290,
A/Turkey/Oregon/1971 I291, C292, W303, M304, I306, Y316, V317, C318, H322, V348, F351, F353, W360, L361, F373, I375, V378, L396,
H7N3 V397, F409, I410, F417, F421, Y422, V423, L425, V436, I443, V444, F446, I464
167 Neuraminidase (EC P03477 I105, V113, V115, F120, I121, F131, F132, L133, L157, C160, A177, W178, A180, A182, C183, L190, L192, I194, A201,
3.2.1.18)/strain V202, A203, L205, M223, V231, C232, Y238, L240, I241, A250, Y252, I254, I257, I262, H274, F275, C278, C280, Y281,
A/Turkey/Ontario/6118/1968 V287, C289, V290, C291, I303, F305, I313, C317, I320, F321, F350, F352, Y354, V358, W359, I360, F372, M374,
H8N4 V375, V382, I394, I395, F407, C422, F423, W424, V425, M427, W438, I444, F446
168 Neuraminidase (EC P03478 I98, I106, V108, F113, V114, F124, F125, L126, L150, V153, W171, A173, A175, C176, M183, I185, V187, A194, Y195,
3.2.1.18)/strain A196, I198, L216, V224, C225, I226, Y231, V233, M234, A243, Y245, I247, V255, H267, I268, C271, C273, Y274,
A/Shearwater/Australia/1972 M277, V280, C282, V283, C284, L296, F298, C310, I313, F346, F348, V354, W355, A356, I360, F368, V370, L371, I378,
H6N5 I384, V390, L391, F403, I415, C418, F419, W420, L421, M423, W435, F443
169 NADH-ubiquinone P03886 Y43, A50, A52, M53, F56
oxidoreductase chain 1 (EC
1.6.5.3)
170 Angiogenin (EC 3.1.27.—) P03950 F33, C50, I53, M54, C63, I66, F69, I70, H71, I77, A79, I80, L93, V102, C105, C116, Y118, V127, V128, V129, P136,
L139
171 Coagulation factor XI P03951 F30, C46, C50, C56, L57, L58, F59, C76, L78, M120, A130, C136, C140, F148, F149, C165, L167, A220, V225, C226,
C230, C236, F238, F239, C255, L257, A274, C283, V289, F301, C317, C321, C327, F329, F330, A337, C346, I366, I388,
W401, V403, L405, C416, I420, I421, I426, L427, A429, A430, V444, Y445, V463, I481, A482, L483, L484, L486,
V490, C500, C514, V516, W519, A535, I537, C545, Y549, I554, C560, A561, A570, L579, C581, V586, H588, L589, V590,
I592, V607, Y608, V611, V612, Y614, I618
172 Catalase (EC 1.11.1.6) P04040 A76, A79, A81, F85, V87, I91, A97, V99, F100, I109, A110, V111, F113, A117, F132, V134, F136, W143, L145, I152,
F153, F154, I155, I159, F164, W183, W186, L193, V196, F200, I205, H209, M212, L222, V230, C232, F234, Y236, A250,
L265, F266, A268, W277, F279, I281, M284, A289, F294, L299, V313, L316, V317, L318, V329, I332, A333, I343,
L351, L355, V375, V443, Y447, L459, C460, I463, A464, L467, A478, V479, F482, V485, Y489, I493, L496, L497
173 RAF proto-oncogene P04049 I58, V60, L62, V72, L78, C81, L82, L86, A97, V98, A118, L126, V128, C152, C165, C176, V180, C184, V372, I405, V420,
serine/threonine-protein I446, A449, A453, M456, L459, H466, M469, L476, V482, I484, F487, A513, V516, V531, Y534, V537, L538, M542,
kinase (EC 2.7.11.1) M581, V585, C588, F599, I606
174 Glucosylceramidase (EC P04062 V54, C55, C57, F76, L108, F120, A123, M124, A127, A128, A129, I132, A139, L142, L143, L144, Y147, F148, I153,
3.2.1.45) Y155, I157, I158, V160, M162, A163, C165, F167, A175, L183, L199, I200, A203, L213, L214, A215, L224, H245,
W248, A249, Y251, F252, F255, L256, Y259, L264, A268, V269, A271, C287, L288, F290, F298, I299, L303, L318, M319,
L320, A331, V334, A340, I347, A348, V349, H350, A357, L363, L375, F376, A377, A380, C381, V382, W396, Y402, I406,
I407, V414, W417, L422, A423, L424, V437, I441, I442, V443, F450, M455, F456, H458, L459, H461, F462, I466,
V473, A485, V486, A487, L488, A495, V496, V497, V498, V499, L500, L509, I511, L519, I528, H529, Y531, W533
175 Vitamin K-dependent P04070 C105, C131, L212, V227, V228, L229, A240, V241, L242, V248, L249, A251, C254, V263, L265, L280, I300, A301,
protein C (EC 3.4.21.69) L302, L303, V339, I363, I365, C373, A388, M406, A408, V417, L419, V434, Y435, V438, I445, I449
176 Cystatin-B P04080 A20, V23, L27, F54, I55, V57, V65, H66, L67, V69, L82
177 Trefoil factor 1 P04155 C51, C57, C68, F69
178 Major prion protein P04156 I139, Y150, Y157, V161, Y163, F175, V176, C179, V180, I182, I184, M205, M206, V209, V210, M213, C214
179 Superoxide dismutase [Mn], P04179 L38, I42, I46, M47, H50, H54, H55, V59, L62, A72, I82, L88, H98, F101, W102, L105, L117, A120, I121, F131, L135,
mitochondrial (EC 1.15.1.1) W147, W149, L150, C164, L170, L179, L180, I182, V184, W185, A188, Y189, Y200, L201, I204, V207, I208, W210,
V213, Y217
180 Phosphatidylcholine-sterol P04180 V49, I50, L51, V52, L60, A62, A117, V133, V149, L152, V163, A165, A166, Y168, L184, V188, M191, V199, F200, L201,
acyltransferase (EC 2.3.1.43) I202, L206, C208, L209, H210, L211, L212, F214, L215, F230, I231, A235, I241, M244, A248, I261, F289, I290, F305,
F306, L309, L328, V333, V335, C337, L338, Y339, V372, A373, C380, W383, L396, M404, V405, I414, L418
181 HLA class II P04233 C213, V253
histocompatibility antigen
gamma chain
182 T-cell surface glycoprotein P04234 V33, V35, C37, Y71
CD3 delta chain
183 von Willebrand factor P04275 V815, C827, C829, C849, C851, C1272, L1276, L1278, V1279, F1280, L1281, L1282, F1293, L1296, F1299, V1300,
M1303, M1304, L1307, V1314, V1316, A1317, V1318, V1319, Y1321, I1329, L1340, A1344, V1347, A1355, V1360,
L1361, F1369, A1377, I1380, L1382, L1383, L1384, M1385, A1386, F1397, V1401, L1404, I1410, V1411, I1412,
V1414, I1416, A1420, I1425, I1428, F1438, L1440, V1443, L1446, I1453, V1454, L1457, L1497, V1499, A1500,
F1501, V1502, L1503, F1514, F1520, M1521, V1524, I1525, M1528, I1535, V1537, V1539, L1540, Y1542, Y1550,
I1561, V1565, A1581, L1582, L1585, A1600, V1604, Y1605, M1606, V1607, V1625, V1626, I1628, V1630, I1642,
L1657, A1661, V1665, L1666, C1670, L1690, V1692, I1693, L1694, L1695, L1696, F1707, F1713, A1714, F1717,
I1718, A1721, V1732, L1733, Y1735, V1743, L1754, V1758, M1761, I1770, A1773, L1774, A1777, L1781, A1795,
V1796, V1797, I1798, L1799, V1800, V1808, A1812, A1815, V1822, I1825, I1827, L1836, L1839, L1857, V1861,
L1871, C2724, L2786, C2804
184 Argininosuccinate lyase P04424 L34, V39, A44, Y45, L49, I63, L67, V70, I88, H89, A91, L96, A104, L107, V118, L121, M125, C129, L132, L136, W137,
L139, I140, M143, V144, A147, F155, L161, W169, I173, L174, A177, L180, L187, V190, I194, L197, L199, L216,
L220, F222, A232, F238, V239, A240, F242, L243, W245, A246, C249, M250, L253, M256, A257, L260, F268, F270,
V271, L273, L293, I296, V303, L310, L325, A331, V332, V335, M339, L343, A346, V349, I350, L353, M360, A363,
M368, L369, L373, A374, Y375, L377, A387, A390, A394, A398, L405, L413, F420, V424, V434, A444, V448
185 HLA class II P04440 Y36, A46, F47, F53, L54, Y57, A65, F67, F74, W88, L95, V101, C106, L118, V126, L136, L141, L142, V143, C144,
histocompatibility antigen, V146, F149, W158, V169, V186, L188, V197, Y198, C200, V202
DP beta 1 chain
186 Envelope glycoprotein P04578 A55, V65, A70, M95, V101, M104, I108, W112, V120, C131, I154, I165, L193, H216, A221, A224, I225, G235, C239,
gp160/group M subtype B V242, I251, L259, L260, V270, I284, I285, V286, L288, V292, I294, C296, M326, C331, I333, W338, L342, I345, A346,
(isolate HXB2) (HIV-1) L349, I359, I360, F361, H374, F376, C378, F383, C385, L390, F391, L416, C418, I423, I424, V430, A433, M434, I449,
L452, L453, L454, I467, F468, W479, L483, Y486, V489, I491, V505, I548, V549, L555, L556, A558, I559, A561, L565,
L566, V570, I573, L576, I580, L602, A607, I635, I642, W666, W680, M687, I688, V698
187 Receptor tyrosine-protein P04626 H42, M45, L46, Y50, C53, V56, L60, L62, L65, F73, L74, I77, V80, Y83, V84, L85, I86, A87, V91, V94, L96, L99, I101,
kinase erbB-2 (EC 2.7.10.1) V102, A113, L114, A115, V116, L137, L140, L142, L145, I148, V153, I155, L161, C162, Y163, I172, F173, C204, W205,
C227, C240, A241, A242, L304, C331, L345, A355, V356, I361, F364, C367, I370, L374, A375, F376, L397, F400, L403,
I406, L410, I412, L422, F425, L428, V430, I431, A440, L443, L445, L448, I450, L453, L455, L461, L465, A466,
L467, I468, H469, L474, C475, F476, V477, L494, C504, C520, W521, C540, C576
188 High affinity nerve growth P04629 L103, A110, L117, L122, L138, C215, L249, L251, V254, L258, C265, A267, V282, C300, I301, L346, L348, L361,
factor receptor (EC 2.7.10.1) A363, A376
189 Hemagglutinin [Cleaved P04661 I19, C20, I21, V32, V42, V49, F57, C58, I60, I66, L68, C71, F73, A74, W76, I77, L78, C83, L86, W92, Y94, I95, V96,
into: Hemagglutinin HA1 Y107, L117, F121, V124, F127, F133, A149, C151, F153, M163, V164, L166, I176, V188, L189, I190, V191, W192, I194,
chain; Hemagglutinin HA2 H195, H196, Y207, V214, V216, Y221, M242, F244, Y245, I248, V249, I255, F257, F263, L264, A265, Y268, A269, F270,
chain]/strain I272, L280, C294, H308, H311, I315, L327, A347, Y364, A386, L460, L468, H484, C486, C490
A/Duck/England/1/1956
H11N6
190 Heat shock protein beta-1 P04792 V6, F8, L10, V97, L99, V101, A105, V118, I120, V148, L163, V165, A167
191 Cytochrome b-245 heavy P04839 A394, V398, V404, M405, L406, V407, V413, F416, I419, V423, L436, F441, Y442, F454, L458, F473, F520, I532,
chain (EC 1.—.—.—) V534, F535, L546
192 Insulin-like growth factor I P05019 L58, A61, L62, F73, I91, C95, C100, L105, Y108, C109, A110
193 Fructose-bisphosphate P05062 L16, I19, A20, I23, V24, I30, L31, A32, A33, M40, L44, F59, I62, L63, F64, V66, I70, I74, V77, I78, L79, L84, F94, I97,
aldolase B (EC 4.1.2.13) L98, V104, V105, I107, L109, L131, C135, Y138, V143, F145, W148, A150, L152, L162, A163, I164, A168, A170, L171,
A172, Y174, A175, C178, L183, V184, I186, V187, C202, V209, L210, V213, A216, L217, L228, L229, V234, Y244,
A250, A252, V254, A256, L257, V261, V265, I268, C269, F270, A280, L282, L284, I287, L298, F300, Y302, A305, L306,
A308, A310, A313, W314, F328, M329, A332, A334, A338, L357
194 Amyloid beta A4 protein P05067 I34, A35, L41, M43, Y72, C73, V85, I94, W97, C117, C133, W150, A154, C158, C174, F179, V182, F184, V185, C186,
C291, C316, C337, V375, L442, L453, Y476, A479, V490, L494, Y497, V498, A500, A523, I537, L548, A555, I558,
I666, V669, H684, L688, V689
195 Arginase-1 (EC 3.5.3.1) P05089 I8, I10, I11, A13, F15, V24, V30, L31, L36, L40, V67, V73, A76, L80, A81, V84, A85, V87, L95, V96, L97, H101, L103,
A104, I105, I108, H111, H115, L118, V120, I121, W122, V123, A125, I129, L140, V145, L148, L149, L152, I169, A171,
I174, V175, Y176, I177, L179, L190, F198, V211, M212, L219, I227, H228, L229, F231, V233, L236, A243, L252, I260,
I264, L273, I275, M276, V278, V293, A296, I299, A302, C303, F304
196 Aldehyde dehydrogenase, P05091 C36, I39, F40, A48, F54, V68, A69, V76, A79, V80, A82, A83, A85, W93, L104, L105, L108, A109, L111, I112, Y118,
mitochondrial (EC 1.2.1.3) L119, A120, A121, L122, L125, L139, V142, L143, C145, L146, Y149, A150, A153, V178, C179, L189, L190, M191,
A193, L196, A199, L200, A201, V205, V206, V207, M208, V210, L216, A218, L219, Y220, V221, A222, L224, I225, A228,
V234, V235, I237, V238, A245, I249, A250, V255, V258, A259, I270, A273, A274, I293, I294, A303, A307, H308, A310,
L311, F312, F313, C318, C319, C320, A321, F326, V327, F335, A343, I370, Y373, I374, F397, I398, V402, F403,
V406, I412, A413, I417, V421, M422, I424, L425, F427, I430, V433, V434, L444, A445, A446, A447, V448, F449, L459,
A478, F482, L494, L499, Y502
197 Integrin beta-3 P05106 C31, C39, C42, L43, C49, A50, W51, C52, C64, L70, C75, V109, I114, L116, L118, F126, I128, V130, V133, V138, I140,
Y141, Y142, L143, M144, L146, M150, I157, L160, L164, A165, M168, I177, F179, A181, F182, V183, Y190, Y192, A198,
C203, C210, Y216, L220, L222, F229, V233, F249, A251, I252, M253, A255, C258, I262, L271, L272, V273, F274, I291,
M313, Y315, M321, L325, L332, I333, F334, A335, V336, Y344, I351, L359, V366, I370, A373, Y374, V381, L383, L392,
A398, C400, I406, L409, C412, L415, V421, F423, I425, A427, V429, F440, I442, L451, V453, V455, C461, C474,
C497, C499, C512, C521, C547, C562, C584, C593, C601, C624, V641, C661, C681, C689, V691, F693, L705
198 Integrin beta-2 P05107 C25, V30, C33, C36, I37, C43, W45, C46, C62, L68, C73, L98, V103, L105, L107, A113, F115, V117, F119, I127, L129,
Y130, Y131, L132, M133, L135, M139, V146, L149, L153, L154, A156, L157, I166, F168, F171, V172, F179, V180,
C191, C198, F204, F217, V221, I226, L237, A239, M240, M241, V243, A244, C246, I250, V255, L258, L259, V260, F261,
A262, I278, Y293, Y301, L307, L311, I316, I319, F320, A321, V322, Y330, L333, I337, A341, L345, V352, I356, A359,
V367, L369, L378, Y382, C400, V403, I409, F411, V413, V415, A417, F426, I428, A430, V437, V439, V441, C445,
C459, C467, C481, C483, C497, C506, C534, C549, C557, A572, C573, C582, C590, C612, A629, C662, V672, Y674,
I687, V689
199 Interleukin-4 P05112 L31, I34, L38, L41, C48, I56, F69, C70, A72, A73, V75, L76, C89, H100, L103, L107, L110, L114, A118, L133, F136,
L137, L140, M144
200 Interleukin-5 P05113 V84, L87, L91
201 Plasminogen activator P05121 V31, A32, A35, F38, V40, V42, F43, V46, A47, V55, V56, F57, Y60, V62, A63, V65, L66, A67, M68, L69, L71, I81, M85,
inhibitor 1 I89, M94, A95, L101, L105, I114, A119, I120, F121, V122, L128, F132, F136, F140, V144, V147, F149, A155, I159,
V163, I171, L174, L175, V180, L186, V187, L188, V189, A191, L192, F194, W198, F202, L211, F212, M224, M225, F231,
Y244, I246, L247, L249, Y251, L256, M258, F259, I260, A261, A262, L270, L273, L277, A279, I282, W285, L296, V297,
L298, F301, V307, L309, L313, L316, M318, M321, F329, L332, L338, V340, A343, L344, V347, I349, V351, A358,
A363, V364, I365, V366, A368, M377, F381, L382, F383, V384, V385, H387, V393, L394, F395, M396, V399, M400
202 Protein kinase C gamma P05129 L120, V386, A461, I476, W538, L544
type
203 Plasma protease C1 inhibitor P05155 L142, A145, F149, L153, Y154, A168, F169, I174, A175, L177, L178, L193, L197, F213, V218, I224, F225, L230,
F236, I262, V266, I274, L278, L281, V288, L290, A292, I293, L295, F313, M325, Y330, A333, A342, V344, L347,
L353, L355, V356, M370, L374, L386, M409, M413, L430, M441, H443, L447, L449, V454, A456, A457, A458, A459,
A461, L478, F479, V480, L481, F488, V490, F491, M492
204 Complement factor I (EC P05156 C33, V74, A76, C86, F100, V129, I140, A150, V152, A153, C154, A163, C181, L182, V184, C186, L193, A210, C214,
3.4.21.45) C229, C241, C247, L254, C256, C266, I357, C365, I368, I375, L376, A378, A379, L382, I430, A431, L432, I433, A452,
C467, L491, M508, C510, A511, L529, V530, C531, V540, W541, V543, V558, V562
205 Alkaline phosphatase, tissue- P05186 L46, A51, V54, I55, M56, F57, L58, A69, A70, L87, M89, A96, A111, A114, A116, Y117, L118, A123, V128, V130, I150,
nonspecific isozyme L151, A154, V161, I163, V164, V169, A172, A179, A182, M192, A196, I204, A205, L208, M209, I215, V217, I218,
M219, M226, L252, V253, W256, I269, L275, L278, V283, L286, L287, L289, F290, M295, M312, V315, A316, L320,
F327, F328, L329, L330, V331, I336, H340, A345, A348, L349, A352, V353, M355, A358, I359, A362, L372, V374,
V375, A377, H379, I395, A412, I413, V459, V461, A468, L471, V480, V483, M484, A485, A487, I490
206 Interleukin-6 P05231 I53, I57, I60, I64, L67, A86, L92, C111, I115, I116, L119, F122, V124, Y125, L126, Y128, L129, A140, V143, L150,
I151, L154, I164, L179, M189, I194, L195, F198, F201, L202, A208
207 60S acidic ribosomal protein P05386 A8, C9, A13, L16, I28, I32, F47
P1
208 T-cell surface glycoprotein P05540 A222, F224, F226, L239, F255, V262, L283, I285, A293, L298, L300, V311, L313, V314, V315, M316, L326, C328,
CD4 V330, L340, L342, I358, W368, C370
209 Integrin beta-1 P05556 C27, A32, C38, I39, C45, C64, I114, L119, L121, L123, F131, L133, I143, L145, Y146, Y147, L148, M149, L151, M155,
V162, L169, M173, I182, F184, F187, V188, Y195, I196, C213, Y219, F232, V236, F252, A254, I255, M256, V258, A259,
C261, I265, V270, L273, L274, V275, F276, I293, Y316, L322, L326, I331, I334, F335, A336, V337, Y345, L348, I352,
L360, V367, I371, I372, V382, L384, C415, I418, F426, I428, I430, I445, V454, V456, L458
210 Gag-Pol polyprotein/group P05961 L8, W16, I19, L21, Y29, V34, A37, L41, L50, L51, C57, I60, L61, L64, L75, L78, V82, A83, L85, Y86, C87, V88, I94, A100,
M subtype B (isolate MN) I104, W158, V161, V162, F167, V171, I172, F175, A182, L187, M190, L191, V194, A199, A200, L204, I208, A212, I239,
(HIV-1) A240, W252, V261, Y265, I269, L273, I276, V277, I285, F296, Y299, V300, F303, Y304, L307, A309, L325, C333,
L337, M350, C353, C395, A405, C416, L499, I507, I509, A516, L518, V526, L527, M530, V550, Y553, I556, I558, I560,
C561, A565, V569, L570, V571, I578, I579, L583, L584, L591, V603, I624, A626, L627, I630, C631, I640, I643, V653,
F654, A655, I656, L667, V668, F670, L673, V683, A691, L693, V699, V701, L702, V704, A707, Y708, F709, V711,
L713, F717, A722, F723, I725, I728, Y737, Y739, V741, L742, W746, A751, I752, F753, M757, I760, L761, F764, L780,
Y781, V782, L786, H791, I795, L798, H801, L802, L803, F807, F820, W822, M823, Y825, L827, W832, V834, L839,
W845, V847, I850, L853, L857, A860, I863, Y864, I867, L872, L876, L888, A892, L896, A897, L903, L918, I919, A920,
V922, W930, Y932, I934, L942, A948, A953, V958, L961, A964, V965, I968, I973, V974, F982, L984, I986, W991,
W994, W995, A1001, W1003, I1004, W1007, V1016, W1019, I1027, F1033, V1035, A1039, A1048, Y1050, L1062, L1072,
A1074, I1075, H1076, L1077, A1078, L1079, V1086, I1088, V1089, A1095, I1099, V1111, I1114, I1115, L1118,
V1124, L1126, V1141, V1145, A1161, M1175, A1186, W1214, V1225, I1226, L1227, A1229, V1230, H1231, I1237,
F1253, L1254, L1257, A1258, V1279, C1283, L1311, I1314, A1328, V1329, A1332, V1333, I1344, A1349, I1353,
A1358, I1361, V1378
211 Collagen alpha-2 P05997 C64
212 T-cell surface glycoprotein P06127 F33, A35, C44, L48, V50, L52, V59, C60, W64, A77, V80, C81, L90, L92, I105, I106, C107, F114, C125, L128, L130,
CD5 C132, L133, V289, V291, L300, C301, W312, V315, C316, C321, C350, C360, V365
213 Insulin receptor P06213 L29, C35, I40, L47, L50, C53, V55, I56, L60, M65, L81, M83, I84, L88, L90, V93, L99, L102, F103, L106, V108, I109,
A119, L120, I122, M125, L128, L131, L133, L136, V144, I146, L152, I163, L164, C186, C209, W210, C223, C228, C235,
C239, C252, A254, F275, W278, C286, V305, L326, I348, A354, L357, C360, I363, L367, I369, I371, L381, L385, I388,
I391, Y394, L395, I397, L406, F408, F409, L412, I415, F427, A429, L435, L438, W439, L446, I448, L453, F455, H456,
L461, I466, M469, I512, L514, W516, L532, A537, M580, I591, V593, A608, I638, L640, V657, I809, I820, L822, A824,
C825, V867, H868, V886, V900, C911, V923, I925, A927, F942, V944
214 Tyrosine-protein kinase Lck P06239 V66, L88, A100, I111, A137, L141, F151, L152, I153, L165, V167, I183, I193, L205, Y209, L216, L220, V240, L245,
(EC 2.7.10.2) L247, V270, V272, L275, F285, A289, L295, L300, L303, A305, V306, V307, I312, I314, I315, L324, L328, L341, L342,
M344, A345, I348, A349, M352, I355, I361, H362, L365, A367, A368, I370, V372, C378, I380, A381, F383, A386, A408,
A411, F417, V423, W424, F426, I428, L429, L430, I433, V449, L453, C465, L469, M473, C476, W477, F487, L490,
V493, L494
215 Alpha-galactosidase A (EC P06280 W44, H46, C63, I64, L68, F69, M72, A73, M76, W81, Y86, L89, C90, I91, C94, W95, M96, L120, A121, V124, L129, L131,
3.2.1.22) I133, Y134, A135, V137, Y152, A156, F159, V164, L167, F169, L180, Y184, M187, A190, V199, Y200, C202, I219,
C223, H225, W226, I232, I239, I242, L243, I253, W262, M267, L268, V269, I270, V281, M284, A285, L286, W287, A288,
I289, M290, A291, A292, L294, M296, A307, L311, V316, I319, F337, V339, W340, A348, A350, V351, A352, M353,
I354, I367, V369, L372, A377, C378, A381, C382, I384, L403, I407, V413, L414, L415, L417
216 HLA class II P06340 H50, F58, V60, A78, A87, I89, L131, I132, C133, V135, I138, W147, F174, L177, V180, Y187, C189, V191, H193
histocompatibility antigen,
DO alpha chain
217 Gelsolin P06396 F59, I70, W71, V73, L78, V81, L85, F89, A94, Y95, V96, I97, L98, V101, L112, H113, W115, A127, A128, L135, A143,
F157, A173, L189, F190, V192, V198, A200, F210, C215, F216, I217, L218, L220, I224, W227, L238, A240, V243,
I247, G254, G264, M270, L271, P276, A279, L280, A282, G283, A292, A298, L300, V303, M310, A316, F321, A322, L326,
C331, F332, I333, L334, I342, F343, V344, A358, L359, A362, F365, I366, V377, V379, L380, F389, F392, A434, M439,
I449, I452, F468, Y474, I475, I476, Y478, Y480, I489, I490, W493, V526, H534, L535, L538, F539, M544, I545, I546,
L565, F566, V568, A578, L588, A593, F594, V595, L596, A602, L604, W605, A610, A618, L621, L622, V632, F641,
A644, L645, L657, L669, A671, C672, V680, L693, A694, V698, M699, L700, L701, V707, F708, V709, W710, A723,
L724, A727, I744, V747, F756
218 Complement C2 (EC P06681 L47, A82, C89, Y107, V113, C144, C151, A160, V173, C191, I462, M573, V697
3.4.21.43)
219 Complement C5 P06684 A691, C703, C728, A731, C735, C736, A739
220 Glycogen phosphorylase, P06737 I16, V25, L28, F32, L36, F54, A55, L56, A57, V60, L64, V83, Y84, Y85, L86, L88, F90, L96, M100, I101, L105, A108,
liver form (EC 2.4.1.1) C109, I113, L118, L123, L132, L137, L140, A141, A142, C143, F144, L145, M148, A149, L151, L153, A154, A155,
Y156, Y158, I160, Y162, V201, F203, V222, A224, V239, M242, L244, W245, A247, A273, I276, L280, L294, Y298, F299,
V300, V301, A302, A303, L305, I308, I309, F317, F327, F330, V334, A335, I336, L338, A344, L345, A346, I347, L350,
M351, F354, I357, L360, A365, L368, F373, A374, Y375, V380, W388, L392, V393, L396, L397, H400, I403, I404, I407,
I415, L418, M429, L431, I432, I440, M442, A443, L445, C446, I447, A452, V453, V456, A457, I459, H460, V464, F469,
F472, L475, I487, W492, L493, L494, A501, L503, I504, Y512, V513, L516, L519, L522, H523, F531, L532, V538,
L544, F546, L550, M563, F564, V566, I571, Y574, L578, L579, C581, L582, H583, V584, I585, I591, V604, I605, I606,
A610, A611, M616, A617, I620, I621, L623, I624, V627, V630, V631, M636, V637, L641, V643, I644, L646, V651, L653,
A654, V657, I658, A660, L663, I667, A670, M680, F682, M683, L684, A687, L688, I690, A696, M700, A701, F712,
A729, L736, L739, V742, I743, I746, F759, I762, L766, F772, F775, Y778, Y781, V782, C784, V788, Y792, V802,
L803, I806, A807, F812, I818, Y821, A822, W826
221 Glucose-6-phosphate P06744 A2, L4, F10, L13, W16, L26, F40, I51, V53, Y55, L59, V60, V64, M67, L68, L71, A72, V77, A79, A80, M84, A97, V98, L99,
isomerase H100, V101, A102, L103, I111, V118, V125, M129, F132, C133, V136, I149, V152, I153, I155, M166, V167, A170,
L171, V184, I192, L205, F206, I207, I208, A209, F213, A222, A225, F229, A233, A238, V239, H242, F243, V244,
A245, L246, V253, F256, I258, F264, F266, W269, V270, Y274, L276, W277, A279, I280, L282, I284, A285, L286, F293,
L296, L297, A300, M303, F307, L312, A316, V318, L319, L320, A321, L322, L323, I325, W326, A337, M338, L339,
Y341, L345, F348, F352, V379, Y392, I395, C404, F406, L407, I408, F429, L436, M437, A445, L463, I477, F479, L482,
M486, L487, A489, L490, V491, A492, M493, Y494, H496, I498, F499, V500, I503, I504, W505
222 Tumor necrosis factor P06804 A93, V95, L127, V137, V141, F143, L154, H156, V158, C179, L204, L210, A212, F230, V232
223 Beta-hexosaminidase P06865 W24, Y37, V60, L61, A64, L90, V94, L95, V96, V97, Y116, L118, I120, C125, L127, V132, W133, A135, L136, L139, F142,
subunit alpha (EC 3.2.1.52) I156, I161, H169, L172, L173, L174, L181, I186, L190, V192, M193, L198, V200, F201, H202, W203, H204, L205,
V206, F211, F216, L221, Y234, V239, V242, A246, I251, V253, L254, A255, F257, L264, W266, L273, V290, F300,
M301, F304, F305, V308, F312, L317, H318, L319, F326, W329, I335, M339, L351, F354, Y355, I356, L359, L360, V363,
Y366, V371, V372, W373, V376, I389, V391, V398, Y400, L404, V407, A414, L415, L416, W420, L422, F434, Y435,
A457, C458, M459, L469, L473, W474, A477, A479, V480, A481, L484, W485, A496, L500, F503, L507, V519
224 Thrombomodulin P07204 C369, C388, C390, C413, C439, C464
225 Vitamin K-dependent P07225 C212, C241, C265, C267
protein S
226 Prostate-specific antigen P07288 I25, V40, V42, V53, L54, V55, V60, L61, A63, A64, C66, I73, L75, F90, V92, L121, L123, L124, L126, L132, A135, V136,
C152, A154, F165, V174, L176, C184, C198, A199, L217, C219, L223, I226, L242, Y243, V246
227 Cathepsin D (EC 3.4.23.5) P07339 L71, I83, I85, F92, V94, V95, W104, V105, C117, Y123, L147, V156, F179, F190, F195, I198, L199, M201, V214, F215,
[Cleaved into: Cathepsin D L218, F229, A268, W270, V272, L274, V277, V279, L285, A292, V294, M301, V308, L311, A317, I327, I338, L340,
light chain; Cathepsin D L342, L349, Y354, F370, L382, L385, V388, F389, I390, Y394, V396, F397, V404, F406, A407
heavy chain]
228 Trypsin-1 (EC 3.4.21.4) P07477 I24, V39, L41, L52, W57, V58, V59, A61, C64, I69, V71, L73, V80, L81, F87, I88, I108, M109, L110, I111, L113, I119,
V123, I126, L128, C139, I141, W144, C160, A163, C171, A173, Y175, F184, C185, V186, V204, C206, L210, V213, V214,
V228, Y229, V232, Y235, V236, I239
229 Decorin P07585 V65, C67, V75, L86, L88, I93, I96, F101, L107, L110, L112, I117, A124, F125, L128, L131, L134, L136, L144, L152,
L155, A157, I162, V165, F170, L173, M176, I179, L181, L186, A195, F196, M199, L202, I205, I207, A208, I212, I215,
L223, L226, L228, I233, V236, L241, L244, L247, L250, L252, I257, L265, L271, L274, L276, L281, L288, I294, V297,
L299, I304, F312, C313, Y324, V327, L329, A352
230 Prosaposin P07602 C66, V69, V70, A73, I86, L90, C94, V110, I117, L118, V131, C132, C230, C265, C271, V317, C318, L321, V325, I338,
M345, C346, C357, V360, I368, L369, V381, C382, V411, C412, L415, V416, L419, I432, L436, C451, F454, L462, L466,
M470, V475, C476, A481
231 Beta-hexosaminidase P07686 A55, W57, L70, C91, L93, L94, A97, V124, L127, V129, I131, A139, Y149, L151, V153, A158, L160, A162, V165, W166,
subunit beta (EC 3.2.1.52) A168, L169, L172, F175, I189, I194, H202, I205, L206, I207, L214, I219, L223, A225, M226, F228, F231, V233, L234,
H235, W236, H237, I238, V239, F244, I249, L254, Y266, V271, V274, A278, I283, L286, F289, L296, W298, L305,
I322, L333, F336, F337, I340, F344, I349, H350, L351, F358, W361, I367, M371, L383, F386, Y387, I388, V391, L392,
I395, I398, I403, V404, W405, V421, V423, Y429, L433, V436, V443, I444, L445, W449, L451, Y463, Y464, A486, C487,
L502, W503, A506, A508, V509, L513, W514, A525, L529, H532, M536, I541, A548
232 Uromodulin P07911 C106, C315, V357, F369, A424
233 Proto-oncogene tyrosine- P07949 Y30, F31, Y36, L40, V42, L50, V53, L68, L72, L80, I86, L95, L97, L109, V121, L123, V125, A143, V145, F147, C166,
protein kinase receptor Ret F174, F185, C197, V223, L229, L239, A241, V242, C243, V245, F258, V260, V262, Y263, A269, Y314, F329, L358, L372
(EC 2.7.10.1)
234 Fumarate hydratase, P07954 V62, A70, V92, I93, A95, F96, I98, L99, A102, A103, A104, V106, A117, A119, I120, A123, A124, V127, L138, V140,
mitochondrial V153, V156, I157, A161, I162, V175, V181, F191, A194, M195, H196, I197, A198, A199, A200, V203, L207, L211, L214,
L218, A220, F225, I228, I229, I231, V240, L242, L244, F248, Y251, V255, A258, I262, M266, I269, L272, A273, A274,
A278, F289, V293, A294, V297, L303, A308, L315, A317, H318, A320, L321, L324, M328, A332, L335, I338, A339,
I342, L356, L358, C377, M380, V383, A384, V387, M388, V392, V394, V407, M411, M412, I413, V416, L417, A420,
L422, L423, F430, C434, V435, V436, I438, A440, I445, M449, L455, L459, A468, I471, A475, L482, A486, L492,
F497
235 Gap junction beta-1 protein P08034 F51, C60, C64, H73, C168, V170, C179
236 Rhodopsin P08100 V11, Y26, W35, F103, C110, L112, I179, C185
237 Beta-microseminoprotein P08118 C38, C57, C60, C62, I67, C84, V97
238 Annexin A6 P08133 A26, L29, A32, M33, I43, L44, I47, V58, Y62, L70, I71, L74, L85, I86, V87, L89, M90, A98, I101, A104, I105, C114, L115,
I116, I118, L119, M127, L130, A133, Y134, L142, I146, I147, M157, L158, V159, L162, V177, V181, L184, A187, F199,
I200, I202, L203, L211, V214, F215, Y218, I226, I230, L241, M242, L243, A244, V245, V246, C248, I249, F256, A257,
L260, A263, M264, L274, I275, I277, M278, V279, L284, M286, L287, I289, I292, F293, L301, I305, L317, L318, L320,
V338, A339, W343, V357, A369, L372, A375, M376, I386, I387, I390, I401, F405, L413, M414, L417, L428, I429,
L432, M433, Y439, A441, W44, A447, M448, A457, L458, I461, L462, A463, I470, I473, A476, Y477, L485, L489, I500,
L501, A505, A519, A523, V525, A526, I529, L530, I532, F547, M548, I550, L551, L559, V562, F563, F566, V574, I578,
A589, F590, A592, I593, V594, V597, L602, F604, A605, L608, M612, L622, I625, M626, I632, L634, L635, I637,
F641, L649, I653, A664, L665, L666, L668, C669
239 Multidrug resistance protein P08183 A58, M75, L107, M111, Y118, V125, A129, F135, C137, A139, A140, I144, I147, F151, F152, A154, I155, M156, I160,
1 (EC 3.6.3.44) L171, L175, V179, I182, I186, A198, V206, L214, I218, A233, A250, A254, V257, A260, V264, A266, F267, Y277, L281,
A284, A292, A301, A302, A308, A311, A313, F314, L332, V334, F335, V338, A348, A358, A362, I365, I369, I375,
L392, V397, L410, L413, V417, V423, A424, L425, V426, C431, L439, M440, V451, I458, I461, V463, L466, I470, V473,
L479, F480, I484, I488, I500, V504, A507, A509, I513, V524, I539, A540, I541, A542, A544, I551, L553, L554, A557,
V569, A572, L573, A576, I583, I585, V592, I598, A599, F601, L615, Y622, I700, C717, A718, I735, I736, L754, L758,
F759, L762, A780, L784, L788, V792, F793, M796, L797, L818, A822, V825, A828, A834, A841, L857, A897, A900,
I901, F904, V907, F916, A935, C956, A961, L976, V977, F983, A1001, A1005, H1007, I1008, V1035, F1037, V1040,
F1042, L1053, L1056, V1060, L1066, A1067, L1068, V1069, V1079, L1082, L1083, V1094, I1101, L1104, V1106, L1109,
L1113, V1116, F1123, A1128, I1131, I1145, A1148, A1149, A1152, I1154, Y1165, V1169, A1185, I1186, A1187,
L1190, L1198, L1199, V1214, A1217, C1227, I1228, I1230, I1237, I1243, V1244, V1245, L1260, Y1267
240 Mineralocorticoid receptor P08235 C603, V605, V617, C620, C623, F627, A630, C645, I647, A657, C658, C663, M668, L742, A752, L765, L769, L772,
M777, W783, A784, L787, F790, L801, W806, L809, F812, L814, L827, A830, L833, F835, C849, I855, F859, L862,
L864, F866, Y869, I871, M872, V874, L875, L876, L877, L878, F892, M895, L903, V907, L924, L927, L928, M931,
F943, V954, L960, I964
241 Beta-glucuronidase (EC P08236 W45, F47, L68, V99, W100, Y101, V119, V120, I123, A130, V132, L147, I168, I170, A171, I172, L176, F208, Y211,
3.2.1.31) L214, V218, L220, V244, L258, V260, L262, V282, W288, L303, V305, L307, A309, V324, F336, I338, F345, H346, V348,
L373, L376, A378, A380, F381, Y386, Y388, M395, V402, V403, I404, C407, L412, H426, M430, V433, A442, V444,
M445, W446, V448, A449, A459, L463, M465, V466, V479, V482, A493, V498, I517, L521, F525, I536, I537, Y541,
A543, Y561, L565, L566, Y569, L573, V581, L585, I586, F589, F592, V601, I608, F609, A618, A619, L622, Y626
242 ATP-dependent 6- P08237 I18, A19, V20, L21, A27, M30, A32, A33, V34, A36, V37, V38, A46, V48, V51, L58, V59, V73, L77, A101, A102, L105,
phosphofructokinase, muscle L113, C114, V115, I116, L122, F128, L135, V159, L161, V162, I165, F169, I176, A181, I185, M186, V189, A196, F203,
type V204, L205, V207, C212, L215, A216, L217, F229, I230, L243, C244, L247, I260, I261, V262, A263, A266, I279, V283,
V284, V293, L296, A307, L312, A320, V321, L324, L325, A333, V335, V336, L348, V358, A370, A389, A404, V405,
M406, V408, A412, A413, M415, A417, A418, V419, V423, V433, L434, V435, V436, F440, V456, I481, V494, I495,
I496, A501, Y502, L506, C519, F522, V523, V524, I525, A527, V533, V540, A542, A545, C550, C553, A560, V567,
F568, I569, I570, C577, L580, A581, A584, L586, A587, I595, L605, V609, L612, M616, L624, V625, L626, I640,
Y644, A676, M679, A683, M684, M687, I691, A702, V710, L711, V723, L726, W742, L745
243 Neutrophil elastase (EC P08246 I30, V45, L47, A57, L59, V65, M66, A68, A69, V72, A73, A79, V80, V82, L84, I118, V119, I120, L121, V133, A153, M154,
3.4.21.37) W156, A166, L172, V174, C187, L206, V207, C208, I212, I215, A216, C223, A231, F232, A233, V235, I242
244 72 kDa type IV collagenase P08253 A50, L54, C60, L74, M77, L83, I124, L135, V140, A143, F144, A147, F148, W151, L157, A167, I169, I171, F173, F184,
(EC 3.4.24.24) A192, F195, F207, L212, W213, V221, V223, Y225, G226, A228, C233, F235, F237, C247, W258, C259, C274, A286,
C291, F295, C305, W316, C317, C332, A347, C349, F353, F355, W374, C375, A376, A379, Y381, W387, C390, L397,
F398, V400, A401, A402, F405, H407, A408, M409, L411, A419, L420, M421, A422, Y427, L433, I441, L444, I478,
A479, I485, F487, F488, I493, W494, A522, V523, Y524, A526, V533, F534, F535, Y543, L556, V568, A570, A571,
F572, I582, F583, I606, L617, A619, V620, V621, F631, F632, L640, W657
245 Neuraminidase (EC P08326 I104, V112, V114, F119, V120, F130, F131, L132, L156, V159, A176, W177, A179, A181, C182, M189, V191, V193,
3.2.1.18)/strain A200, V201, A202, V204, L222, C231, I232, Y237, V239, M240, A249, Y251, I253, A256, I261, H273, I274, C277,
A/Equine/Kentucky/1/1981 C279, Y280, V286, C288, V289, C290, L302, I304, C316, I319, F349, F351, V357, W358, A359, I363, F371, I373, I374,
I393, I394, L397, F406, L418, C421, F422, W423, V424, M426, W437, I443, M445
246 Neprilysin (EC 3.4.24.11) P08473 A66, L69, F83, A87, C88, L118, L122, A132, A136, A138, L139, L157, L158, I164, W167, V169, W174, A184, A187,
I188, A189, L191, I201, L203, I217, H218, I219, Y231, A244, Y245, F248, M249, V252, A253, I256, M273, V276,
L279, I283, A284, A286, M303, L305, A306, I308, L314, I316, W323, F326, I330, M331, I336, V344, V345, V346,
A348, Y351, L352, L355, L359, L367, M371, W373, I376, V380, L383, Y387, F394, C411, A412, V415, M419, A422, V423,
Y427, V440, I444, I447, V450, F451, L455, A463, A469, A473, A475, L493, Y497, L500, A539, I553, V554, F555, F564,
F565, L573, I578, M580, I582, I586, F590, F615, M622, Y626, A634, I649, A650, A658, A661, Y662, L685, F686, F687,
L688, F690, A691, V693, C695, A703, I719, L723, F729, C735, M741, V749
247 Integrin alpha-IIb P08514 L34, Y42, F50, L54, H57, I66, V67, V68, A70, V84, C87, L115, L124, V128, I135, V136, A137, C138, A139, W144,
V146, A153, V158, C161, L163, A164, A172, Y174, C198, A200, L212, V213, L214, A216, L225, L226, A227, A229,
V231, I234, L243, V247, Y284, V285, V286, A288, W291, A297, V298, I300, L301, F320, A325, V329, L337, L338, V339,
A341, A354, V356, V359, Y360, L361, L378, F387, A392, L394, L397, I405, A406, V407, A408, V420, V422, L438,
A447, F448, Y463, L466, I467, V468, A470, V476, A477, V478, Y479, A481, V485, I518, V522, L535, A537, L539, L541,
V552, A581, I596, L598, L600, C633, L662, L664, A675, A681, V682, A688, A693, V715, V716, M724, M734, V736,
F750, L752, I754, A775, Y815, L817, V825, L828, I832, V919, C921, M926, V934, L940, L945, L955, A959, V982,
L986
248 Apolipoprotein P08519 C4145, W4148, C4173, C4184
249 Pleckstrin P08567 V26, V27, L28, I33, F35, I48, V68, F69, I71, H79, F81, W92, I96, I100, M133, I140, C155, F156, V161, I162, L165, A181,
L184, L190, A200, F209, A215, Y217, F219, L251, F266, L268, A273, L275, H276, I290, L292, L314, F315, I317, L327,
A329, W338, I342, A345
250 Collagen alpha-2 P08572 L1492, L1518, Y1519, L1531, Y1565, W1566, L1567, I1587, C1590, V1592, C1593, A1595, F1625, H1628, A1630,
C1646, F1655, I1656, C1658, C1665, C1705, V1707, C1708, M1709
251 Receptor-type tyrosine- P08575 C226, F246, A248, V279, I281, L295, V297, V301, I319, L321, F340, C365, I369, I408, W410, F420, L422, L444, L455,
protein phosphatase C (EC L457, A459, A463, M499, V501, L518, V520, F537, F550, A552, F554
3.1.3.48)
252 Hepatocyte growth factor P08581 A48, I62, F63, L64, A66, I70, Y71, V72, L73, L78, L130, I131, C133, C141, H144, I154, I161, C175, V176, V177, I193,
receptor F195, F196, V197, I214, V216, L219, I235, V237, Y245, I259, Y260, F261, L262, I278, I279, F281, L288, Y291, M294,
L296, C298, I299, L300, F314, I316, L317, A319, L329, A330, I341, F343, G344, V345, F346, A347, A354, A361, M362,
C363, F365, I367, V370, V383, L386, H388, F389, L424, L429, F430, L439, I442, I452, A453, L455, F462, V465, V467,
H476, V477, V486, L503, V504, I505, I510, I513, L515, L518, C520, C529, C541, C561, A573, L581, I583, F588, V603,
L622, C624, I638, I640, F652, I659
253 Complement factor H P08603 C21, A48, Y50, V62, C66, C80, V108, A110, C129, C141, V144, C146, V174, F176, M190, C192, C205, Y227, F233,
Y235, A249, C251, C325, V347, Y355, I372, C389, F391, L394, V414, L422, V429, C431, Y467, A473, C494, C505,
L532, I551, C553, C569, Y587, L593, F595, V609, C611, L636, V655, Y657, I671, C673, C684, Y709, V715, F717, I731,
C733, C744, C753, L761, F771, I777, C792, C870, I876, C915, C926, V942, V955, A971, C973, C984, C1048, Y1067,
V1073, V1089, C1109, I1120, V1134, Y1136, C1138, L1144, I1150, C1152, C1167, I1169, M1174, I1179, L1181, L1189,
V1197, F1199, C1218, L1223, C1228
254 Genome polyprotein P08617 W91, V106, V107, L110, V117, L121, A127, F129, I131, V135, L147, I148, A150, M151, V152, V202, I207, V209, L213,
[Cleaved into: Protein V227, A229, F231, A306, V326, Y329, F331, L346, A347, C350, W356, L360, L376, C379, V418, A443, I444, I448,
VP0/genotype IB (isolate Y450, C451, V465, L471, F600, Y628, V644, V702, I722, Y727, L734, C738, L841, F869, L880, I907, I911, F914, L953,
HM175) (HHAV) (Human L954, I962, V1528, V1533, F1535, V1537, M1548, A1550, L1551, V1553, L1558, L1559, V1560, F1576, F1578, V1604,
hepatitis A virus (isolate V1605, L1606, M1607, V1609, I1618, I1623, A1631, A1636, L1638, V1639, L1654, V1676, A1679, W1680, M1690,
Human/Australia/ A1694, L1695, V1696, I1706, L1707, I1709, A1712, L1718, V1719, A1720, L1722, V1723
HM175/1976))
255 40S ribosomal protein S17 P08708 V9, A13, I17, C35, I50, A51, V54, I61
256 Coagulation factor VII (EC P08709 C141, I213, C219, V228, L229, L230, L242, V248, V249, A251, A252, L264, A266, L268, V285, V288, I289, Y294,
3.4.21.21) I303, A304, L305, L306, V318, L321, L333, V341, W344, A354, V362, C370, M387, F388, C389, A390, H408, A409,
H411, L418, I421, V422, V436, Y437, V440, Y443, I444, W446, L447, L450, A463
257 Interleukin-6 receptor P08887 L45, C47, V50, V58, W60, V86, Y94, C96, V130, C132, L148, L149, V150, C176, L178, Y188, V190, M192, V194, L234,
subunit alpha V236, L251, F253, L255, Y257, A259, V270, L273, I279, A282, H288, V290, L292, A294
258 Dihydropteridine reductase P09417 V13, L14, V15, C26, V27, F30, V37, A38, V40, V67, V71, V80, A82, I83, L84, C85, M107, L121, A122, L131, L132,
(EC 1.5.1.34) L134, A153, V157, H158, C161, A176, A177, I178, A179, V180, L181, L208, F212, L227, I228, V230
259 Fructose-1,6-bisphosphatase P09467 L14, F17, V18, L34, L38, A41, V42, I45, A52, L74, V82, L86, A91, C93, V94, L95, V96, V106, V115, V116, C117, F118,
1 L121, V133, I136, F137, I139, Y140, A153, A162, A163, Y165, A166, L174, V175, L176, A177, V182, C184, F185,
F194, A223, V224, Y227, V250, V253, L257, I262, F263, L264, L278, L279, Y280, C282, M285, A286, Y287, V288,
M289, A292, A296, V303, L304, I311, A315, V317, I318, L319, V325, F328, V331
260 Macrophage colony- P09603 C39, I43, L51, L54, F69, V70, L75, C80, A85, V89, M93, L112, L115, L119, C122, C134, L145, V149, V152, F153,
stimulating factor 1 L160, F167, C171
261 Platelet-derived growth P09619 L52, C54, V60, W62, L85, L90, C100, Y117, I118, F119, V120, I147, C149, V151, L160, C190, V225, I231, L233,
factor receptor beta C235, V237, L265, L276, I278, Y289, C291, V293, I308
262 Pro-cathepsin H [Cleaved P09668 V240, V279
into: Cathepsin H mini
chain; Cathepsin H (EC
3.4.22.16); Cathepsin H
heavy chain; Cathepsin H
light chain]
263 Ubiquitin carboxyl-terminal P09936 M12, L13, V16, L17, L20, V22, A23, V42, C47, A48, L49, L50, L51, L52, F53, I67, M82, I86, L95, I96, H97, A98, V99,
hydrolase isozyme L1 L114, F117, L118, A130, F133, I139, A142, H143, V146, A147, F160, H161, F162, I163, L164, F165, L172, Y173, L175,
M179, L193, L194, A197, A198, C201, V212, V217, A218, L219, C220
264 Leukotriene A-4 hydrolase P09960 C8, V16, C17, L22, V28, L35, A39, L41, V43, L53, L55, V65, I67, M87, I89, A94, L95, I103, I105, F107, A115, L116,
L119, Y131, L132, F133, C136, A138, C141, A143, L145, C147, V153, Y157, A159, V161, V163, L167, A169, L170,
A173, F192, I198, C200, Y201, L202, A204, V206, V207, V221, V228, F235, M241, L242, A245, L248, L259, L260, V261,
L262, F266, C275, L276, F278, V279, L283, I294, A295, I298, H300, W302, V307, W312, W316, L317, H321, Y324, L325,
H328, I329, A343, L344, L350, L366, L370, V382, F388, A389, L390, L391, F392, L394, L397, L398, F404, F407, L408,
Y411, V412, I420, W425, L429, L440, W448, C469, W476, F487, F503, L504, I518, M521, F527, I535, W539, L540,
L542, C543, I544, A551, L554, A555, A559, F567, L571, F572, L575, A585, Y589, H597, L603, V604
265 Complement C4-A P0C0L4 L24, L25, F26, V31, L37, V39, V41, L43, V52, V56, L76, L87, A94, L110, V111, A112, I130, L132, I149, Y150, V156,
Y158, V160, A162, I174, V176, V178, I215, A217, F219, F231, V233, F241, I252, I266, A268, I271, V276, A280, V282,
L286, L305, F319, V340, A341, A343, I345, L378, A382, L386, V390, V403, V405, A407, V409, V431, I433, I435, L444,
A450, V462, L473, L491, M508, L510, V529, V533, F541, F543, V544, A545, F546, Y547, V560, A564, L633, V646,
F647, L652, F654, I687, C703, A720, C735, A739, F833, L835, L837, L855, L863, V865, V867, V889, V897, V901, V913,
V914, A915, V927, L931, V945, L948, V978, V980, A994, L995, V1000, A1001, M1015, I1016, L1018, A1019, A1023,
A1024, Y1027, L1028, A1045, I1049, I1056, Y1066, A1067, A1068, W1077, L1078, A1080, V1082, L1083, V1085,
L1086, A1089, L1107, F1117, L1132, V1139, A1140, L1141, A1143, F1144, V1145, I1147, A1148, L1149, V1168,
A1175, L1179, A1192, A1193, A1194, I1195, A1197, A1199, L1200, A1205, L1210, A1213, L1217, W1230, I1262,
A1266, Y1267, A1268, L1269, H1271, A1282, A1285, L1289, V1306, I1307, A1308, A1311, L1327, V1329, L1331,
L1358, I1366, V1368, L1378, Y1384, L1501, V1512, V1522, L1524, F1538, A1540, L1578, A1617, Y1625, F1627,
V1629, F1643, I1647, F1667, V1669, Y1683, L1684, I1685, M1686, Y1701
266 Complement C4-B P0C0L5 L43, I149, I271, L305, V409, L510, A564, L652, I1366
267 Serum amyloid A-1 protein P0DJI8 M35, A38, F54, A56, A62, A72, A73, A99, A100
268 Serum amyloid A-2 protein P0DJI9 A72, A99
269 Transcriptional activator P10071 C548, L563, C578
GLI3
270 HLA class I P10321 M29, Y31, A35, F46, V52, F57, V58, F60, A73, W75, V76, Y83, Y91, A95, L102, L105, L119, M122, C125, L127, Y142,
histocompatibility antigen, Y147, I148, L150, L154, W157, A163, A164, A176, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223,
Cw-7 alpha chain L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, M285, H287
271 Hemagglutinin [Cleaved P10448 A50, L61, C62, C65, L71, A74, L75, C80, A87, V89, V91, C102, I112, L115, L119, A135, Y143, I145, C151, F161,
into: Hemagglutinin HA1 M164, A165, W166, A167, V168, V180, V182, I193, V195, W196, H199, M206, Y210, F218, I251, V253, I266, Y268, I272,
chain; Hemagglutinin HA2 L273, L274, V278, A281, I288, C300, L301, H302, A385, A511
chain]/strain B/Bonn/1943
272 Lysosomal protective P10619 L54, H61, L62, H63, Y64, W65, F66, V67, V78, V79, L80, W81, L82, L91, L94, L95, H98, F101, W117, A121, V123, L124,
protein (EC 3.4.16.5) Y125, V132, F134, V149, A156, L157, F160, F164, Y167, L172, F173, L174, Y179, A180, I182, Y183, I184, L187,
A188, V189, V191, L202, V204, L208, L218, V219, A222, L236, F248, C256, L260, V263, V267, V297, V298, M327,
A337, Y340, L341, V346, L350, W359, C362, V366, Y370, M377, Y381, L382, L384, L385, L393, L394, Y395, M401,
F411, V412, W426, V428, V441, I447, A448, F449, L450, I452, A455, H457, V459, A466, A467, M470, F471, F474
273 Mast/stem cell growth factor P10721 I54, L56, C58, W66, Y95, C97, I107, V109, V111, F118, V134, C136, I170, I172, V175, L184, C186, V188, F200, L202,
receptor Kit V213, F229, V231, C233, I235, W246, A273, L275, A280, F288, C290, A292, V325, L333, V335, Y337, A339, W348,
Y362, V374, L377, L382, Y390, F392, V394, F405, V407, V409, C428, A430, A431, W440, V473, V474, V489, C491,
A493
274 60 kDa heat shock protein, P10809 A36, M40, V44, L47, A48, V51, V80, A81, A95, V98, V101, A102, A116, V118, L119, A120, I123, A124, I140, V144,
mitochondrial A147, V148, A150, V151, L155, V162, I168, V171, A172, A176, I182, I186, A189, M190, F219, F228, C237, A242,
V244, L245, L246, I251, I257, V258, A260, L271, V272, I273, I274, A275, V278, A282, L286, V297, V298, A299, V300,
A302, L313, M316, A317, A319, V324, F325, L342, V345, V348, I349, V350, L357, L358, I371, I374, A395, L397, V401,
A402, V403, L404, V406, V421, A424, A427, A430, A431, V437, L438, C442, A443, L444, L445, C447, I465, I467, I468,
L472, A476, A480, I490, V491, I494, A507, M513, I519, A528, L529, A532, A533, A536, L539
275 Thyroid hormone receptor P10828 C107, V109, A114, C124, C127, F131, C151, I153, C164, F166, C169, M174, V225, A228, H229, L246, A268, F269,
beta I280, V283, F286, A287, L290, F293, L304, C308, C309, I312, L315, A318, L328, A335, V336, V349, F354, A371, L372,
L373, A375, L377, L378, M379, I392, F399, A402, F403, L421, V425, L428, I431, A436, F439, M442, C446, L456
276 Growth hormone receptor P10912 F64, C66, L84, C112, F114, Y125, I127, L129, C140, V143, V147, L160, A169, I171, V173, M188, L194, V217, L220,
V228, V230, V249
211 78 kDa glucose-regulated P11021 V30, V31, I33, L35, C41, V42, V44, I53, Y65, V66, A67, F68, A80, V92, L98, I99, V108, V119, Y127, I128, V130, A141,
protein I145, A147, L150, M153, A157, A159, V165, A168, V169, V170, V172, A174, A183, A187, A191, L193, V195, M196,
A204, A205, A206, I207, A208, L211, I220, L221, V222, F223, L225, F230, V232, L234, L235, I237, F242, V244,
V245, A246, L253, F258, V262, M263, F266, I267, Y270, V278, A284, V285, L288, V292, A295, L299, A305, I307, I309,
Y313, F318, L322, F327, L334, F335, M339, V342, V345, L346, I356, I359, V360, L361, V362, I371, V375, F379, A393,
V394, A395, A398, A399, V400, A402, L422, I426, I437, F451, V461, I463, V465, Y466, I487, I497, V499, F501, L509,
V511, A513, V542, L565, Y568, A569, L572, M594, A597, V598, L605, F616, L623, V627
278 Hemagglutinin [Cleaved P11132 V5, I19, C20, I21, A25, V32, I35, V42, I48, L49, L57, C58, L60, L66, L68, C71, V73, A74, W76, L77, L78, C83, F86, W92,
into: Hemagglutinin HA1 Y94, I95, V96, Y107, L117, L120, L121, F127, I133, A150, C151, Y153, V163, V164, W165, L166, I176, L188, L189,
chain; Hemagglutinin HA2 I190, L191, W192, I194, H195, H196, A201, Y207, Y213, V214, V216, L221, M242, F244, F245, I248, L249, I255, F257,
chain]/strain F263, I264, A265, Y268, A269, Y270, I272, I280, M281, C290, C294, A300, I301, H308, H311, I315, V322, L327, L329,
A/Duck/Ireland/113/1983 A330, A349, M361, Y366, A388, I389, A440, L452, V459, L462, V466, L470, C481, H486, C488, C492, M493, A510
H5N8
279 Solute carrier family 2, P11166 I40, Y44, W65, I297, F298
facilitated glucose
transporter member 1
280 Solute carrier family 2, P11168 L10, A17, Y26, V30, I31, I38, Y42, W97, V101, F104, M128, A131, A139, M142, I154, Y164, C165, L171, V172, M174,
facilitated glucose Y175, I176, I179, W218, L221, L222, A229, L234, L236, L246, A256, L260, L263, M276, L294, I304, V306, A307,
transporter member 2 L310, I322, Y325, I329, F330, V360, F369, M373, M376, C379, A380, M383, A403, I404, F407, V408, I418, M422,
V423, A424, F427, A435, A439, V465, F466, L473, I495
281 Pyruvate dehydrogenase E1 P11177 A38, I39, M43, L47, V53, L55, V60, A61, I82, A93, I95, A96, A100, I107, C108, F110, F113, A119, V123, A127, V140,
component subunit beta, I142, F144, F162, A163, Y166, V174, V175, A183, L186, I187, A190, V197, V198, V199, L200, Y206, F212, A216,
mitochondrial I225, I237, V239, V240, V246, A252, A253, L256, C263, V265, I266, M268, I279, V283, L289, V290, I305, I309, A314,
I337, I349, I353
282 Integrin alpha-M P11215 F27, F34, V46, V47, V48, A50, L63, C66, A84, M87, L89, L102, L103, A104, C105, C123, F124, I151, A152, F153, L154,
I155, I161, M169, F172, V173, V176, M177, L180, F187, L189, M190, Y192, F200, F202, F205, V215, A228, I231,
V234, L238, I252, L253, V254, V255, I256, V271, I272, A275, V280, I281, V284, I285, V287, A290, F291, L300, I303,
A304, F313, V315, F318, A320, L321, L328, I332, F333, L365, L366, V378, I390, M399, L404, I411, L419, V420, L421,
A423, V432, A433, M434, F435, V464, V466, L474, V475, L476, I477, A479, V491, V493, C494, L509, F520, L527,
V530, V538, A539, I540, A542, A551, V552, Y553, L554, F555, I571, A572, L580, F583, L601, V603, A605, V609, L612,
V617, L618, V631, V657, I670, V674, L680, A689, F691, L714, L716, L718, I729, L731, L733, L748, F764, L792,
V794, F800, V802, V804, V806, V818, F820, F822, C864, I881, F883, A889, L895, L897, A899, V925, M951, H953, Y955,
V957, L965, I967, L969, F971, V973, L977, I982, W983, L1014, V1020, A1025, C1027, C1032, F1037, I1039, F1043,
A1045, L1047, L1051, W1055, L1064, I1066, A1070, I1072, V1097
283 Glycogen phosphorylase, P11217 V16, V25, L28, L36, F54, A55, A57, V60, L64, I83, Y84, Y85, L86, L88, F90, L96, M100, V101, L105, A108, C109, L118,
muscle form (EC 2.4.1.1) L123, L132, L137, L140, A141, A142, C143, F144, M148, A149, L151, L153, A154, A155, Y156, Y158, I160, Y162,
V201, F203, V222, A224, V238, V239, M242, L244, W245, A247, A273, I276, L280, L294, Y298, F299, V300, V301,
A302, A303, L305, I308, I309, F317, F327, F330, V334, I336, L338, L345, A346, I347, L350, M351, L354, L357,
M360, A365, V368, C373, A374, Y375, V380, W388, L392, L393, L396, L397, H400, I403, I404, I407, F411, V415, A418,
M429, L431, V432, I440, M442, A443, L445, C446, I447, A448, A452, V453, V456, A457, I459, H460, L464, F469, F472,
L475, I487, W492, L493, V494, A501, V503, I504, F512, I513, L516, L519, L522, L523, F531, I532, V538, L544, F546,
L550, L563, F564, I566, I571, Y574, L578, L579, C581, L582, H583, V584, I585, I591, V604, M605, I606, A610, A611,
M616, A617, I620, I621, L623, V624, A626, I627, V630, V631, A636, V637, L641, V643, L646, L653, A654, V657, I658,
A660, A661, L663, I667, A670, M680, F682, M683, L684, A687, L688, I690, A696, M700, A701, F712, A729, I736,
L739, V742, I743, L746, F759, I762, M765, L766, F772, F775, Y778, Y781, I782, C784, V788, Y792, V802, I803, I806,
A807, F812, I818, A819, Y821, A822, W826
284 Spike glycoprotein/strain P11224 I16, V44, L79, V87, Y96, I104, A106, V108, L111, A121, I128, F132, V140, I148, A150, V152, C153, I157, C158, C165,
A59 (MHV-A59) (Murine F202, H205, A215, F226, Y240, V241, F244, I245, C246, Y258, Y268, L269, F270, I292, V319, C354, F385, F393, V395,
hepatitis virus) L411, A414, Y416, Y429, A468, C471, V474, C479, C481, A482, A499, A529, I534, I549, F550, A551, L585, F594,
F619, A641, L652, C658, V661, C682, C706, C775, C780, C786, V800, L876, Y891, V900, V906, I912, A931, V952,
I956, A980, A994, I998, I1030, A1039, L1046, I1047, A1053, L1054, L1067, A1072, A1075, V1079, I1099, V1103,
Y1111, F1112, I1113, H1114
285 Acetylcholine receptor P11230 W141, C151, Y157, C165, V329
subunit beta
286 Ras-related protein Ral-A P11233 H15, V17, I18, M19, V20, V25, L30, F34, V55, L57, V62, I64, I66, L67, A70, I78, F83, F89, L90, C91, V92, F93, I95,
F101, F107, I111, V114, V120, F122, L123, L124, V125, L131, V137, A142, A146, A158, V164, V167, F168, L171, M172,
I175, M180
287 Medium-chain specific acyl- P11310 A27, A52, F55, A56, I60, A65, I78, A81, M87, I91, C106, L107, I108, L112, A113, C116, V119, A122, M131, I133, Y145,
CoA dehydrogenase, L146, M149, C156, A157, C159, I172, I185, I192, W200, Y201, F202, L203, L204, A205, A215, A218, F219, F222, I223,
mitochondrial V224, I233, C244, I250, F252, V255, V257, L263, V272, A273, A276, V283, V284, A285, A286, A288, V289, L291,
A292, A295, A299, A303, M326, V330, A333, M335, A340, A341, A354, A357, A361, A365, L368, A369, A372, V387,
A394, Y397
288 Fibroblast growth factor P11362 L51, L53, C55, V86, V88, C101, F114, V174, F176, C178, I215, M217, V220, Y228, C230, V232, F275, C277, C341,
receptor 1 A343, L356
289 Glucose-6-phosphate 1- P11413 I33, F34, I35, I36, M37, A39, A44, I48, I52, W53, L55, I67, V68, Y70, A71, F88, F101, Y118, L121, M125, A134, L137,
dehydrogenase F138, Y139, L140, Y147, V150, I154, C158, I167, I168, I196, Y197, I199, Y202, M207, I230, C232, V233, L235,
I255, I256, V259, M260, L264, L265, M267, L268, C269, V271, A272, M273, V284, Y308, Y322, F337, A338, A339,
V340, V341, L342, V344, W349, F354, I355, L356, C358, A361, A367, V369, L371, V391, I392, V394, A399, L440,
V444, F452, I464, F465, A492
290 Dystrophin P11532 V25, F29, L40, L50, L51, L54, V77, A80, L81, L84, I99, I111, I114, L140, W143, V144, V156, A168, A171, L172, I173,
L196, A199, F200, A203, I228, Y231, I232, L235, Y344, L348, L355, V375, H382, I399, V420, L427, L445, L3053,
V3070, Y3073, M3088, L3098, A3109, L3112, L3115, L3119, L3121, A3129, M3145, I3150, C3153, L3154, Y3158,
V3175, C3178, L3179, W3181, L3182, L3183, F3199, I3204, L3206, C3207, C3229, L3234, L3238, I3242, I3244, V3263,
C3266, W3294, L3295, V3297, L3298
291 C-1-tetrahydrofolate P11586 L20, V24, L38, A39, I40, L41, I53, A60, I63, V81, I85, V94, F97, L98, V114, V124, L135, C152, L155, I156, A168, V169,
synthase, cytoplasmic V170, M181, L185, C195, V206, I211, L212, V213, V214, V222, I227, A231, V233, I234, V256, A261, I268, M278,
A281, L283, M284, A291, L393, V394, A396, L397, V405, F406, A407, V480, L497, I502, F518
292 Cholesteryl ester transfer P11597 A26, V29, A36, A51, V72, I103, V106, V108, I188, I200, I207, F267, L313, V328, V329, A336, C350, F367, V376,
protein F380, L426
293 B-lymphocyte antigen CD20 P11836 F146, L147, L152, I162, I164, C167, Y182, C183
294 Amyloid beta A4 protein P12023 Y476, A479, V490, Y497, L509, F512, A523, I537, L548, M580, L749, M752
295 Collagen alpha-3 P12111 C3112, C3158, C3162
296 Coagulation factor V P12259 V36, A37, A38, V65, Y66, L85, L86, A92, I98, V100, F102, L110, I112, H113, A126, V142, Y150, W152, I154, C167,
I171, Y172, L186, I187, L190, I192, C193, L213, L214, F215, A216, F218, V234, V238, I245, V247, I253, W255, H256,
L257, L258, F267, I269, H270, F271, L276, L288, V289, A296, M298, W306, I308, H315, M320, I324, I354, A355, A356,
Y363, Y391, V394, M395, L431, F435, Y443, Y483, I487, C500, A516, L519, L523, L524, I525, C526, A546, F548,
M586, I589, V593, V608, W610, H611, F612, I621, I624, H629, F631, L643, V651, V653, M655, W661, L663, L675,
F679, I1584, A1585, A1586, V1618, F1620, I1643, I1648, A1650, I1656, V1658, F1660, Y1668, L1670, H1671, A1672,
L1675, Y1677, Y1708, W1710, A1712, A1729, Y1730, L1744, I1745, L1748, I1750, C1751, F1769, V1770, L1771, L1772,
F1776, A1807, I1808, L1818, M1820, V1826, L1828, L1830, I1839, H1840, V1841, V1842, F1844, H1845, L1849,
L1864, L1872, W1882, L1884, V1888, M1896, F1900, I1902, C1907, L1913, A1937, A1947, W1948, I1963, V1971,
F1993, F2032, I2043, L2054, L2056, M2072, A2101, A2111, W2112, A2114, L2123, I2125, I2133, A2135, I2136,
C2141, V2150, Y2153, I2155, F2178, I2196, I2201, V2203, I2212, A2213, L2214, L2216, L2218
297 Low affinity P12318 A41, L53, V58, L60, C62, I73, W75, A94, Y102, C104, L117, L120, L124, V125, L126, L131, F133, I139, L141, C143,
immunoglobulin gamma Fc H144, V154, F156, F157, F172, A177, Y185, C187, I203, V205
region receptor II-a
298 Bone morphogenetic protein P12643 F305, C329, A343, M371, C393, C395
2
299 Bone morphogenetic protein P12644 F317, C341, A355, M383, C405, C407
4
300 Angiotensin-converting P12821 A46, F49, A57, A86, W97, A101, Y105, L117, I121, L132, M147, L172, L176, L185, L186, A188, W189, W192, H193,
enzyme A196, L200, Y204, F207, A214, Y231, L240, Y244, L247, Y251, L254, H255, A256, V258, L262, I271, I277, A279, H280,
L282, A287, W290, I293, V297, L306, V308, M312, A319, M322, F323, A326, F329, F330, L333, F342, F366, F372,
I374, V388, H389, M392, I395, Y397, Y401, L408, F416, A419, I420, V423, L424, L426, L434, L439, Y453, L454, L455,
M457, A458, L459, A463, L465, F467, L470, V471, W474, W492, L495, I502, C503, F513, A515, A517, V521, F531,
V532, V535, L536, F538, F540, H541, L544, C557, I559, A565, L569, L573, V584, L585, A596, L599, Y602, F603,
V606, A649, F652, Y674, Y700, A704, I717, I720, I721, L732, M747, L770, M774, L783, L784, A786, W787, W790,
A794, I798, Y802, Y805, L808, A812, A821, Y829, L838, F842, L845, L848, Y849, L852, H853, A854, V856, A859, L860,
I869, I875, A877, H878, L879, L880, A885, W888, I891, V895, A901, M904, A909, M910, M920, F921, A924, F927,
F928, L931, F940, L946, V956, F964, F970, I972, L983, A986, H987, M990, I993, Y995, Y999, V1004, A1005, L1006,
A1010, F1014, A1017, I1018, V1021, L1022, A1023, L1024, V1026, L1032, L1037, F1051, L1052, M1053, M1055,
A1056, L1057, I1060, A1061, I1063, F1065, Y1067, L1068, V1069, W1072, W1090, L1093, L1100, C1101, F1111, A1115,
I1119, F1129, V1130, I1133, I1134, F1136, F1138, H1139, A1141, L1142, C1143, H1153, C1155, I1157, A1163,
L1167, A1170, M1171, F1175, A1182, M1183, I1186, A1194, A1196, M1197, Y1200, F1201, L1204, L1208
301 Cadherin-1 P12830 C163, I178, V188, V204, F205, L214, V216, L220, Y228, L230, A234, M246, I248, I250, V252, F262, V271, V284, A301,
M316, I326, V328, Y341, L343, V344, V345, A347, A348, A359, A361, I363, V365, L396, L436, L442, L452, V454,
V456, A471, V473, V475, Y508, I542, L548, Y561, A563, I565, A567, L581, L583, I600, I612, I650, L652, I665, L667,
L669, M670, L681, V683
302 Xaa-Pro dipeptidase P12955 V18, L22, F23, L30, C31, L34, I45, V46, V47, F71, H72, W73, A74, F75, V77, C82, V85, I86, V88, L95, F96, V97, L136,
L144, L145, L176, I180, V185, V194, L195, A205, H206, V209, M210, L222, F226, C243, C245, I267, M272, C273,
F275, M277, Y281, F284, A285, I288, F292, V305, Y306, A308, V309, V316, W326, H330, A333, L338, L341, I346,
M354, L359, F363, M364, L368, L372, L394, L397, L403, M407, V408, L409, V411, I415, Y416, L422, A425, F443, V449,
I451, V455, I475
303 Hemagglutinin [Cleaved P13103 I21, C22, V23, V34, V44, I51, Y59, C60, L70, F75, I79, V80, Y96, L97, L119, L122, F123, I126, F129, I135, C151, F167,
into: Hemagglutinin HA1 I177, V189, L190, V191, L192, I195, Y208, V217, M243, I245, I250, I256, F258, F264, L265, A266, Y271, I273, F282,
chain; Hemagglutinin HA2 C295, I302, L328, A348, Y365, A387, L461, L469, H485, C487, C491
chain]/strain
A/Gull/Maryland/704/1977
H13N6
304 Platelet glycoprotein Ib beta P13224 V37, C39, L60, L62, L67, A69, L70, W91, C93, L97, L100, L104, L116, C118, L128, L129, L137
chain
305 C-C motif chemokine 2 P13500 C34, C35, C59, A63, V64, I65, F66, I74, A76, V83
306 Cystic fibrosis P13569 V1240, L1242, L1253, F1257
transmembrane conductance
regulator
307 Integrin alpha-4 P13612 Y44, F52, H59, L67, V69, A71, A74, A87, C91, L106, V142, C144, L160, C165, A196, C198, A200, V212, M213, A215,
L225, V227, V245, L251, F260, V268, V269, A272, H275, A281, Y282, I283, F284, L291, F306, V313, L315, L323, L324,
V325, A327, V339, V341, A349, A366, F368, L375, I378, V386, A387, I388, A390, A399, I400, Y401, Y403, I418,
F430, Y445, A449, V450, A452, A458, V459, L460, L461, V466, F502, M519, L521, F535, V550, A562, A579
308 Sodium/potassium- P13637 H34, M36, V41, A58, L94, A98, C101, V125, V130, V161, I162, V175, V176, L180, V181, A191, L193, I195, C201, V203,
transporting ATPase subunit F234, C239, A244, V247, V248, A264, I278, A289, A310, I312, F313, I317, L326, V332, A338, C346, V354, C364,
alpha-3 L371, M376, A379, M381, W408, A410, L411, I414, A415, L417, C418, A421, V432, A445, L446, V457, L480, I482,
H483, Y493, L494, L495, V496, M497, I504, L512, Y532, L535, F545, C546, H547, L550, L573, C574, F575, V576,
L578, M581, A587, V589, A592, V593, C596, A599, I601, I604, M605, A614, A616, A618, I623, I624, A635, A636, A650,
A652, I678, V679, F680, A681, I691, V692, C695, V702, V709, A714, L715, A718, I720, V722, A723, M724, I739, L740,
F745, V752, L757, I758, Y768, L770, F783, L792, I800, A809, L812, L834, V835, L839, A843, I847, Y859, I862, L863,
F868, L873, W880, C908, A911, F912, F913, V914, I916, V917, V918, V919, L924, I926, C927, L944, L948, A955, L968,
M970, A981, I988, L999, Y1013
309 Delta-aminolevulinic acid P13716 L31, Y33, I35, F36, V37, L50, V53, Y56, L61, L65, V76, L77, I78, F79, V81, A94, A101, A104, I105, L108, L115, V117,
dehydratase C119, V121, C122, L123, H129, C132, L134, L150, A151, V153, A154, Y157, C162, V164, V165, A166, M170, M171,
V175, I178, L182, V193, M194, Y196, A198, F200, A211, A212, A234, V238, L249, M250, V251, V261, V264, H268,
L273, A274, V275, Y276, H277, V278, F282, V300, A303, M304, F307, A310, A312, I315, I316, Y318, Y319, L323,
L324
310 Tissue factor (TF) P13726 A41, F51, L55, Y66, V68, I70, C89, L91, I95, A105, V107, V155, V157, V159, L175, F179, L183, Y185, L187, Y188,
(Coagulation factor III) Y189, F207, I209, V211, F219, V221, A223, V224, I225
311 HLA class I P13747 L26, Y28, H30, F43, V49, F54, V55, F57, M66, A70, W72, M73, Y80, A88, A92, F95, L99, L102, L116, W118, M119,
histocompatibility antigen, C122, L124, F137, Y139, Y144, L145, L147, L151, W154, A160, A161, A174, L181, C185, V186, L189, Y192, L193,
alpha chain E L200, V210, A220, L222, C224, A226, F229, Y230, L236, W238, H245, A266, A267, V268, V269, V270, Y278, C280,
V282, H284
312 HLA class II P13765 F33, V34, F43, V50, F52, V53, F56, L60, V64, F66, F73, W87, L94, A100, C105, V117, V125, L135, L140, L141, H142,
histocompatibility antigen, C143, V145, F148, W157, V168, L187, V196, Y197, C199, V201, W214
DO beta chain
313 Electron transfer P13804 L23, V24, I25, I41, A43, A44, V51, C53, L54, V55, C60, V63, A64, L67, C68, V70, V76, A79, L92, L95, I96, I108, C109,
flavoprotein subunit alpha, A110, L119, V123, A124, A125, I135, F144, V165, F166, V168, V218, V219, L225, F231, L234, L237, A238, A243,
mitochondrial A244, A247, A251, V263, V270, Y275, I276, A277, V278, M290, A298, A305, I307, V323
314 Glycogen [starch] synthase, P13807 V28, L80, Y102, W160, F165, L166, L190, F202, A215, A247, F287, H291, F293, F307, A345, I456, V473, F477, L482,
muscle (EC 2.4.1.11) C500, V504, L592
315 Endothelin-3 P14138 C107, C169
316 Macrophage migration P14174 P2, F4, V6, F19, L23, L27, C57, A58, L62, Y76, L79, L80, L83, L84, L88, I90
inhibitory factor
317 Folate receptor beta P14207 A34, C51, W54, A58, C59, C60, M86, C90, F94, C99, L100, C103, V126, L128, C129, C133, W136, C140, F176, L182,
C183, L186, C203, I204, M206, V219, A220
318 Hepatocyte growth factor P14210 I39, F42, L50, C70, A71, C74, L80, C84, A86, F87, V88, C96, W98, F99, F101, F112, L118, Y136, C149, W152, L172,
C177, C189, F190, C206, Y219, C232, W235, C260, W270, C271, Y272, C283, I285, C288, Y313, W329, C354, W364,
C365, F366, C377, I380, C383, V495, M508, V509, L511, C519, L523, V529, L530, A532, C535, Y544, A546, L548,
I550, L579, V580, L581, M582, L584, V594, I597, C612, V614, L629, A632, L634, C642, I657, C658, A659, C669,
L677, C679, V687, V690, I691, F706, V709, A713, I716
319 Perform-1 P14222 V61, L249, F442
320 D(2) dopamine receptor P14416 V78, F189
(Dopamine D2 receptor)
321 Solute carrier family 2, P14672 L24, A27, A31, Y40, V44, I45, I52, Y56, W81, V85, A86, F88, I99, M112, A119, M126, A129, L138, I145, Y148, L155,
facilitated glucose V156, M158, Y159, V160, I163, A187, W202, L205, L206, V210, A213, V218, L220, L230, A240, L244, L247, L260,
transporter member 4 L278, L288, I290, A291, L294, A305, V306, Y309, I313, F314, V344, H353, L357, M360, C363, A364, M367, A370,
A387, I388, F391, V392, I402, I406, V407, A408, F411, A419, A423, V449, F450, L457, I479
322 Platelet glycoprotein IX P14770 L93
323 Interleukin-1 receptor type 1 P14778 I39, W57, H75, L81, F83, A86, C96, V97, V98, C104, I107, A111, L140, C142, M145, F148, W160, L181, V183, Y194,
C196, A198, I209, I213, F215, V238, L246, C248, V250, W260, L296, I298, I301, F305, F310, C312, F313, A314, L327
324 Matrix metalloproteinase-9 P14780 A45, L49, L74, L78, C99, I121, I137, A140, F141, A144, F145, W148, L154, A164, I166, I168, L187, A189, H190, A191,
F192, A202, F204, W210, V218, P219, F222, A225, C230, F234, G238, C244, W255, C256, C271, A283, C288, F292,
C302, W313, C314, A315, C329, C347, F351, F353, W372, C373, A374, F379, W385, C388, L395, F396, V398, A399,
A400, F403, H405, A406, L407, L409, A417, L418, M419, Y420, F425, L431, I439, A515, A523, L531, L533, F534, I556,
F580, F581, F582, V587, L604, V613, L626, F627, F635, F673, C674, Y679, L702
325 Interleukin-2 receptor P14784 C36, Y38, A42, I44, C46, W48, V61, A63, L88, L98, V101, V104, L106, V108, F124, F127, L130, L132, C148, I150, F167,
subunit beta A169, F206, V208, V210
326 Gamma-aminobutyric acid P14867 V416
receptor subunit alpha-1
327 Protein C-ets-1 P14921 A323, A327, F340, L341, L342, L345, C350, I354, F363, L365, V371, A372, L389, L393, I401, I402, V411, F414, L418,
L429, L433
328 Junction plakoglobin P14923 A140, A162, A163, V166, A174, L179, L185, V186, A188, V189, V190, M193, L209, L212, L219, I222, I228, A230,
L231, V232, V242, A246, I247, L250, L253, A260, V264, L270, M273, F284, L285, A286, C291, L292, L295, A296,
I306, A308, L315, V316, I318, M319, L327, V334, L335, L338, C341, I348, V349, A351, M354, A356, L357, L361, L368,
V369, C372, L373, L376, L379, V382, A383, L389, V392, L393, L396, V397, L400, L408, C410, A411, L415, L418,
V429, V435, L438, I439, A441, A445, I451, A455, V456, A458, L459, L462, A472, V476, I485, V486, L488, L489, L497,
V498, A500, I502, L504, I505, L508, A509, L510, A513, A516, L518, V523, I524, L527, L530, L531, A534, M556, I559,
V560, C563, A566, L567, L570, A571, I580, I586, L588, F589, V590, L592, L593, I600, A604, A605, V607, L608, L611,
A612, A618, A620, I621, A623, A626, L630, L633, L634, A642, A645, A646, V648, L649
329 Leukemia inhibitory factor P15018 L44, I48, L52, L55, A59, L62, Y66, F74, L81, C82, L102, L105, Y106, I108, V109, V110, L112, L116, I119, A130, L133,
L137, L144, L147, L148, V151, L152, C153, L155, C156, V164, C185, L187, L188, Y191, I195, L198
330 Phosphoglycerate mutase 2 P15259 L6, V7, M8, V9, H11, F22, A28, A38, A42, A44, I45, F52, I54, C55, Y56, L60, A63, L67, I70, L71, L87, H91, L95, V112,
(EC 3.1.3.13) M126, I136, Y142, L156, I160, A163, W167, I171, I175, A177, V181, L182, I183, A184, A185, H186, L190, I193,
V194, L197, I205, L210, I214, I216, V217, Y218, L220, V239
331 Interferon gamma receptor 1 P15260 V46, W48, F59, V61, V63, C85, I87, L98, V100, V102, A104, A120, I141, I143, I145, Y172, V174, V176, I187, C200,
C214, V215, A217, I238
332 Arylsulfatase A P15289 I23, V24, L25, I26, F27, A28, L31, L36, L49, Y63, V64, A74, A75, L76, L77, L100, V107, A108, L111, Y116, M120, A121,
W124, L126, I147, Y149, H151, C156, C161, V177, I179, L181, L182, A189, L194, L197, Y201, A205, L208, M209,
A212, F219, F220, L221, Y222, Y223, A224, H226, H227, F238, F247, L251, L254, A257, V258, L261, I265, L275,
V276, F278, A280, V310, A314, L315, A331, L337, L340, A341, A344, L358, F375, Y376, V386, F387, A388, V389, Y394,
A396, H397, C414, H415, P426, L428, L459, C500
333 Beta-1,4- P15291 V154, V178, A179, I180, I181, I182, F184, L191, W194, L195, L198, H199, V201, L202, L207, Y209, I211, Y212, V213,
galactosyltransferase 1 I214, A225, L227, L228, V230, A235, Y241, F244, V245, F246, L251, I252, Y260, H268, I269, A272, V289, A291,
L292, F297, I300, F303, W308, W310, I317, L321, M366, L367, Y376, L386, V392, I394
334 V-type proton ATPase P15313 V47, V52, V53, L54, V57, V66, F68, V80, V83, A88, I89, V90, V92, C106, V117, M121, V125, F126, I147, M163, I164,
subunit B, kidney isoform I168, I171, V173, I177, A178, I183, I185, F186, A188, I196, A197, A198, I200, C201, A204, L206, V207, H217, A222,
I223, V224, F225, A226, A227, M228, F238, F242, V251, C252, L253, F254, L255, I266, I267, L271, A272, L273, A276,
F278, L279, A280, V287, L288, V289, I290, L291, M294, Y297, A298, A300, L301, V304, A306, A307, M321, L325, I328,
Y329, A332, V335, I342, I345, I347, L348, I359, F365, I371, V373, L377, I386, V388, A399, H409, V412, L416,
C419, Y420, V426, F448, L449, F452, F456, I457, V467, L471, W475, L478, F481
335 Folate receptor alpha P15328 C37, L53, C57, W60, A64, C65, C66, W86, M92, C96, F100, C105, L106, C109, V132, L134, C135, C139, W142, C146,
C152, W156, F178, F182, L188, C189, I192, Y197, I210, M212, V225, A226, M233
336 B-lymphocyte antigen CD19 P15391 L36, C38, W52, F83, V87, F94, L96, C97, V113, L188, L196, L198, C200, W214, L225, L228, W240, L246, L248, W281,
W283, L284, W290
337 Granulocyte-macrophage P15509 L47, C60, L62, C81, F94, V96, I128, M134, C136, Y150, L152, C178, F192, V194, C233, W237, F251, Y253, L255, V257,
colony-stimulating factor L270, V294, I296, A298, A299
receptor subunit alpha
338 Membrane cofactor protein P15529 C80, A93, M123, F125, L139, C141, A148, V160, V187, I208, C210, V226, V252, I268, C270, C283
339 Vascular endothelial growth P15692 C52, I61, I72, F73, V78, L80, L92, I106, F122, C213, C225
factor A
340 Immunoglobulin lambda- P15814 W67, C82, V97, L104, V106, L107, V116, A128, A131, L133, C135, L136, M137, F140, Y141, L145, V147, W149, A151,
like polypeptide 1 A174, A175, L179, L181, Y192, C194, V196, H198, V203
341 Arylsulfatase B P15848 L47, V48, F49, L50, L51, A52, L55, V60, L72, V80, Y85, Y86, L98, I105, V122, L128, L132, L133, M142, V143, W146,
L148, C155, Y168, L169, Y175, H178, I184, A193, F196, F215, A219, L232, F233, L234, L236, A237, L238, V241,
Y255, Y266, A267, M269, V270, M273, V277, V280, L284, V294, F295, I296, F297, L321, V326, V329, F331, V332, I348,
H349, I350, L354, L357, A361, V376, I380, I389, L391, L392, A431, A432, I433, L440, L441, C447, L474, F475, L498,
L502, W529
342 Beta-galactoside alpha-2,6- P15907 L109, L144, F160, W165, A178, C184, A185, V187, L193, I202, A207, V208, L209, A214, V223, I229, L231, M232,
sialyltransferase 1 F243, L254, I255, V256, W269, F277, Y281, Y284, F293, I295, L296, M300, L304, L308, M325, L326, I328, I329, I330,
M331, M332, C335, V338, I340, Y341, L344, Y369, L378, V379, L382, I390, L392, A396, L398
343 Desmoplakin P15924 C191, M195, V214, I228, L235, A247, L251, Y255, L258, I275, F312, A343, I347, I364, C367, I368, H371, F381, A385,
Y403, L414, L421, V446, L463, C467, V476, C482, W493, V495, V508, L510, I512, A519, I526, M544, L547, C553,
I560, A562, L568, V623, V1975, A1977, L1980, C1983, V2004, I2018, A2019, A2021, L2031, A2034, L2048, A2051,
A2053, A2054, I2058, V2069, A2072, I2086, A2089, A2092, A2110, M2122, L2124, L2125, A2127, V2134, V2141,
F2142, L2143, A2148, F2172, Y2183, L2186, L2201, V2217, L2222, I2250, I2260, A2261, I2263, A2277, A2288,
L2292, A2294, A2296, A2297, I2301, V2312, A2315, L2329, A2332, V2336, Y2339, A2353, L2367, L2368, A2370,
I2377, H2384, L2386, A2391, F2415, L2424, Y2426, L2429, L2443, L2444, I2619, A2621, I2622, I2631, L2650,
L2651, A2653, C2656, I2660, L2671, A2674, V2679, L2688, A2691, A2694, A2709, A2712, F2726, F2729, L2736,
V2737, A2750, L2774, I2783, Y2785, A2788, A2805
344 Mucin-1 P15941 I1049, F1054, L1058, Y1065, Y1066, L1069, F1086, F1094, V1099, F1107, L1134, V1141
345 P-selectin P16109 W42, W53, C60, L67, V68, A69, L79, Y90, W91, I92, I94, A114, A118, C131, V132, I134, I136, W145, A156, L157,
C158, C168, C194, C226, C244, C288, F290, C306
346 Integrin beta-4 P16144 L1544, V1546, Y1560, V1562, I1577, V1587, F1598, V1600, A1602, I1618
347 Toxin A (EC 3.4.22.—) P16154 L9, A13, Y23, I26, L27, L30, L36, Y45, L48, L51, I55, F58, M59, L71, L74, I78, V82, L97, H98, F99, V106, A110, Y113,
W117, L128, W129, A134, F135, L136, V137, L140, A143, I144, A152, L156, F170, Y171, M175, I178, Y179, F185,
I201, I204, I205, H208, L209, I231, I239, L244, F245, I253, Y254, L258, L259, A266, A267, I270, V271, L273, L274,
A275, L276, V282, Y283, L284, M288, L289, I314, L316, A318, I319, F334, F345, I349, I358, F359, L362, V367, L370,
I372, I374, A375, A385, L386, I387, L394, V398, V402, Y406, L409, L413, A416, F423, F430, L434, F445, L446, I449,
L453, F457, A461, L467, A472, Y473, A476, Y477, F480, L483, L497, F500, A526, L561, V580, Y582, I583, I584, C597,
F600, I608, I609, I610, Y636, I638, L642, V648, V650, F652, I653, F665, L673, I677, F680, I684, I688, V693, V695,
L697, C700, M702, F703, Y713, L717, L718, I721, I725, L729, V732, I737, I739, A741, L756, I764, A769, I770, I780,
A791, I806, L857, V867, L871, L885, I886, F888, V900, F902, I903, F920, Y923, I927, L961, F965, I967, V987, V989,
L991, A993, L1000, I1003, L1009, A1016, L1050, V1068, A1078, I1084, V1122, Y1125, F1126, L1129, L1152, V1153,
I1154, C1169, I1171, A1173, I1204, M1222, L1224, A1227, F1232, L1253, I1256, F1264, I1276, L1279, I1288, I1290,
F1299, I1304, F1317, Y1324, L1326, L1328, I1333, I1337, L1339, W1345, I1346, F1347, V1353, L1383, I1390, L1405,
I1413, L1415, I1416, I1417, I1419, L1430, L1441, I1448, L1451, I1458, A1473, I1474, I1482, L1493, F1503, F1516,
M1517, I1524, I1538, F1540, I1542, V1550, V1552, L1555, L1557, V1561, Y1565, V1569, M1582, F1585, L1586, F1591,
L1594, F1608, L1610, V1611, F1621, F1633, F1646, V1653, V1654, V1655, L1671, Y1675, L1678, V1688, L1689, I1690,
Y1695, I1701, I1714, I1728, L1730, W1739, F1746, I1768, L1769, F1782, L1790, I1793, F1864, L1872, F1883,
F1905, A1906, F1936, F1956, A1961, A1963, A1964, V1965, F1977, F1998, F2006, F2017, F2039, A2040, F2070,
F2090, A2095, A2097, A2098, Y2109, Y2110, F2111, F2132, F2151, F2153, I2158, I2161, F2173, A2174, F2204,
F2224, A2229, A2231, A2232, Y2244, F2245, F2263, F2265, F2287, A2288, F2318, F2338, A2343, A2345, A2346, I2352,
Y2357, F2359, F2380, F2399, F2401, I2406, I2409, F2421, A2422, L2445, F2452, F2472, A2477, V2478, A2479, V2480,
Y2492, F2493, F2512, F2514, F2534, A2535, F2565, F2585, A2590, A2593, I2599, F2604, Y2605, F2606, F2625,
A2626, F2656, F2676, A2681, A2683, A2684, A2685, I2691, F2697, F2698
348 Beta-galactosidase (EC P16278 F41, I51, I55, H56, Y57, W65, L69, M72, A75, A79, I80, V84, W86, H89, V104, F107, L108, A111, H112, L116, V118,
3.2.1.23) I119, L120, Y125, I126, A128, W130, M132, L135, A137, L139, L140, L146, L147, Y154, V158, W161, L162, L165,
L166, M169, L172, L173, V180, I181, V183, Y189, Y199, L200, L203, F207, V215, F218, L228, L236, Y237, V240, A251,
F269, V289, L293, I296, A301, V303, L305, M307, F308, I309, A320, L337, A340, Y347, L350, I353, I354, A387, A388,
L392, F406, F415, V416, Y418, C426, L432, V439, A443, V447, L455, I465, A471, L473, L475, V477, V483, I489,
L495, L499, L501, W509, I511, A519, L524, A550, F551, I558, I571, F573, V581, W582, I583, L588, Y591, L601, V603,
I616, V618, A624, A635, V636, F638
349 Histone H1.5 P16401 I47, L65, I83, L87, L90, L96
350 Cytotoxic T-lymphocyte P16410 V40, A48, A54, F56, C58, Y60, A66, V69, V71, V73, C85, A86, A87, L95, V112, L114, I116, Y127, C129, V131, I149,
protein 4 V151
351 Epithelial cell adhesion P16422 Y32, C48, C66, V68, A122, I144, H150, L162, L176, F180, L185, I191, L195, V207, I209, A213, Y215
molecule
352 Histo-blood group ABO P16442 A92, I94, I116, L118, V120, A122, I123, L130, F133, L134, A137, F141, M142, H145, V147, H148, Y149, Y150, V151,
system transferase F152, M189, M191, I192, F195, C196, F200, V204, Y206, L207, V208, C209, V210, V212, M214, F216, V220, V222,
I224, L225, L228, F229, L232, A254, I256, Y264, Y265, L266, G268, F269, F270, V274, V277, L280, C284, M288, V290,
A298, H305, L306, L310, V318, L319, Y323, L324, W325, L336, L339, F341
353 Thyrotropin receptor P16473 C41, L57, L59, L64, I67, F72, I78, I81, V83, L89, L92, F97, V103, I106, I108, L114, A121, L122, L125, L128, L131, I133,
L144, V147, F154, L156, I158, M164, I167, L175, L180, L182, L184, F189, V192, A196, F197, V205, L207, L213,
A220, L231, V233, L252
354 Interleukin-7 receptor P16871 L55, C57, I73, Y92, I107, V109, L123, V127, F146, V148, V160, V167, A168, I203, V205
subunit alpha
355 Fumarylacetoacetase P16930 L17, V21, F22, I32, V34, A35, I36, I40, L41, L43, I46, F50, L55, F62, L67, F70, M71, A77, A81, L85, L89, L96, L102,
A106, L196, M198, L200, M202, A203, F204, F205, V206, A221, M228, V229, L230, M231, W234, A236, V259, V263,
V264, A268, L269, L287, F295, I297, V301, L303, C315, W324, M326, L327, L330, L345, L346, A347, I351, M362,
L375, V390, I392, C396, I403, F405, C408, V412
356 Alpha-N- P17050 W30, A32, C49, I50, L54, F55, M58, A59, M62, W67, Y72, L75, I77, C80, W81, L91, I102, L105, A106, V109, L116, I118,
acetylgalactosaminidase Y119, A120, M122, V138, A142, F145, V150, L153, L155, Y169, M172, A184, F185, C187, L205, C209, L211, W212,
(EC 3.2.1.49) I218, V225, I228, L229, L239, V242, W248, M253, L254, L255, I256, A268, M270, A271, L272, W273, V275, L276,
A277, A278, L280, M282, I296, L297, M302, I305, I324, V326, Y327, A337, L338, V339, F340, F341, L355, I365,
A368, F386, I390, M397, L400
357 Aspartate aminotransferase, P17174 V34, L36, L51, V53, V54, V57, F80, A84, A88, A95, V104, A112, L113, I115, A117, L120, A121, V134, V136, H144,
cytoplasmic F148, F174, L178, A181, I186, V187, V188, L189, A193, H194, I209, A210, M213, F221, F222, A238, A240, I241, F244,
F251, C253, A254, F257, F261, V268, L271, M288, V292, A304, I306, V307, A308, W320, V324, M327, A328, L338,
L342, I354, M360, F361, L374, I380, L382, I388, V390, L393, L398, V401, A402, A408
358 HLA class I P17693 M29, Y31, A34, A35, F46, A48, V52, F57, V58, F60, M69, A73, W75, V76, Y83, A95, L102, L105, L119, W121, M122,
histocompatibility antigen, C125, L127, Y140, Y142, Y147, L148, L150, L154, W157, A163, A164, V176, A177, L184, C188, V189, L192, Y195,
alpha chain G L196, L203, V213, A223, L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283,
V285, H287
359 Neuronal acetylcholine P17787 V56, L60, L83, W87, L119, A135, V137, I143, W145, A149, F173, I183, L185
receptor subunit beta-2
360 ATP-dependent 6- P17858 I18, V20, L21, A27, M30, A32, A33, V34, A36, V37, A46, V48, I51, L58, V59, V73, I77, A101, A102, L105, L113, C114,
phosphofructokinase, liver V115, I116, L122, F128, L135, A159, L161, V162, I165, F169, I176, A181, I185, M186, I189, A196, F203, V204, L205,
type V207, C212, L215, A216, L217, F229, I230, M243, C244, L247, I260, I261, I262, A263, A266, V279, V283, V284, V293,
L296, A307, L312, A320, V321, L324, L325, A333, V335, V336, L348, V358, A370, A389, A403, I404, L405, V407,
A411, A412, M414, A416, A417, V418, V422, V432, Y433, V434, V435, F439, V455, I480, L493, V494, V495, A500,
Y501, L505, A510, C518, M521, C522, V523, I524, A526, V532, L539, A544, M549, C552, A559, V566, F567, I568,
V569, C576, L579, A580, I585, A586, V594, L604, V608, M611, M615, L623, V624, L625, L639, Y643, L678, A682,
M683, L686, L690, A701, V709, I710, V722, L725, W741, L744
361 Ganglioside GM2 activator P17900 L80, C106, C136, C183
362 Complement receptor type 1 P17927 C43, A52, L69, I84, C86, C99, I121, I127, Y129, A143, C145, V152, I164, C166, V191, Y193, I213, C215, C238, F256,
V262, V278, C280, C493, I534, I571, I577, C595, V641, C665, C688, F706, V712, V728, C730, C943, I984, C986,
C1004, I1021, I1027, A1043, C1045, A1052, I1064, C1066, V1091, Y1093, C1095, I1113, C1115, C1138, F1156, V1162,
V1178, C1180, C1396, I1437, V1480, C1498, V1544, C1568, C1591, F1609, I1615, V1631, C1633
363 Vascular endothelial growth P17948 F135, M148, L154, I156, C158, V160, V167, L169, F192, I194, A197, L205, C207, A209, Y220
factor receptor 1
364 TFIIH basal transcription P18074 L40, M42, L53, A54, M57, A58, L70, Y72, C73, I80, V83, I84, L87, L102, L107, A108, L109, L115, A139, L170, L177,
factor complex helicase C190, Y192, L194, A195, A202, Y209, V231, V232, A236, I239, C243, L251, L256, C259, L263, A298, V309, C375,
XPD subunit (EC 3.6.4.12) L382, A404, L406, C437, A443, I444, I455, I456, L461, L471, F473, M493, I494, Y520, A537, F539, I561, Y584, A594,
L596, L597, V599, A617, I619, M620, F621, V623, A635, A656, A660, V664, A667, M677, V678, F684, W696, A704
365 Toxin B (EC 3.4.22.—) P18177 L9, A13, Y24, I27, L28, L31, M37, Y46, L49, I52, Y59, L72, F75, L79, V83, L98, H99, F100, I107, Y114, W118, V129,
F130, A135, F136, L137, I138, L141, V145, A149, F171, F172, M176, I179, F186, I202, I205, V206, L210, I232, V240,
F246, L254, Y255, L259, V260, W263, A267, A268, I271, L272, I274, A276, L277, M283, Y284, L285, M289, L290, L317,
A319, I320, F335, F346, L350, I359, F360, L363, A368, L371, V373, I375, A376, L387, I388, C395, I399, I403, Y407,
L410, L414, A417, F431, I435, M447, L450, L454, F458, V462, L468, A473, Y474, A476, A477, Y478, L481, F484,
L498, F501, A527, L562, I578, Y580, I581, V582, A594, C595, F598, A599, V606, L607, F608, A618, Y634, I640, I646,
L648, F650, F663, L671, I675, A678, A682, I686, I691, I693, L695, M700, F701, Y711, L715, L716, V719, I723, M727,
I730, I735, V737, A739, L754, I762, I778, V789, F1866, F1888, F1908, A1909, F1938, H1956, F1958, F1979, F1999,
F2019, F2039, A2040, F2069, F2090, A2095, F2305, A2306, F2335, F2355, A2360
366 Vinculin P18206 F4, H5, I9, L13, A17, I20, L70, M74, A77, V81, C85, A91, A92, L95, A104, I109, L116, L124, A129, V131, I134, C138,
L145, A148, Y160, L164, M171, I175, L182, L191, V192, V198, L201, L205, A208, M209, V213, I223, A226, M237, I241,
I244, V247, L248, A269, I273, A280, W283, A298, I299, I302, A306, I321, V335, A353, L360, L363, V367, I384, I388,
A391, I408, A411, A415, A419, I431, I438, L445, V466, L470, L473, A480, A500, A518, C545, V548, L551, L576,
L580, L609, A613, F626, F633, A644, A679, L683, F695, L734, A760, I763, V766, V783, A786, L790, V828, V831, A909,
M956, I966, A970, L973, A977, I987, I988, A990, A991, M994, A995, M998, M1001, L1015, C1018, A1019, I1022,
A1023, A1025, V1029, A1033, A1037, C1040, L1049, V1052, C1053, I1056, L1063, A1071, A1087, L1091, A1095,
L1098, M1099, V1102, V1106, A1109, A1112
367 Interleukin-1 receptor P18510 F38, I40, V56, A57, V73, A80, L81, F82, L83, C91, L92, C94, L103, F123, F125, F136, C147, A149, V156, L158, F171
antagonist protein
368 Cytidine deaminase/strain P19079 L6, A10, A13, A28, A29, L30, L31, A54, A58, L59, A62, L73, A74, V75, A76, A77, C89, I93, V101, V103, V104, V117
168
369 Erythropoietin receptor P19235 A39, L41, L42, L50, C52, F53, L60, C62, F63, W64, F79, Y81, L83, F105, C107, L120, L122, V124, I139, V142, V143,
L144, L145, V152, V162, L164, W166, I178, Y180, V182, V184, L207, F218, A219, V220, A222, M224
370 Lymphocyte function- P19256 F43, V54, W56, V63, A64, L90, I92, L95, Y103, F116, L118, L121, L129, C131, V140, M156, M163, C166
associated antigen 3
371 Vascular cell adhesion P19320 A37, V43, L45, C47, L80, M82, V85, Y93, C95, A97, I108, F115, I133, V135, C137, V139, V142, F145, I150, L152, L178,
protein 1 L193, C195, A197, L199, A325, V331, L333, C335, L368, L370, V373, Y381, C383, V385, I396, F403, V421, V423,
C425, V427, V430, L433, I438, L440, L466, L481, C483, A485, L487
372 Tumor necrosis factor P19438 C59, C62, C72
receptor superfamily
member 1A
373 Hemagglutinin [Cleaved P19694 I25, C26, M27, V38, V48, L54, V55, L63, C64, L70, C76, I78, I79, A82, L83, C88, L91, V98, F99, I100, V106, C109, Y110,
into: Hemagglutinin HA1 F112, Y117, L120, L124, A125, F130, F137, A150, C151, F159, F160, L163, L166, Y191, W193, V195, H196, H197,
chain; Hemagglutinin HA2 Y208, V215, V217, I243, F245, Y246, I249, V250, L255, I256, F258, L264, I265, A266, Y271, I288, C295, H296, V302,
chain]/strain V323, L330, A331, A348, W357, Y365, A387, A439, L461, L469, C480, F481, I483, H485, C487, C491, I492, I495,
A/Budgerigar/Hokkaido/1/1977 A509
H4N6
374 Nuclear factor NF-kappa-B P19838 F57, L69, V84, A93, V95, I96, V97, L99, V100, H109, A110, H111, L113, I122, C123, A127, V133, V134, L139, L153,
p105 subunit M157, A160, C161, L170, L175, I196, A199, A200, V212, L214, F216, A218, A238, I239, A247, L250, V262, I268,
L270, L271, I282, F284, I311, V312, F313, V329, V331, L333, F347, Y349, Y350, M808, L819, Y820, L823, L835, A836,
F848, L858, M859, L872, A875, L876, A884, I888
375 C-X-C motif chemokine 3 P19876 C45, I52, C69, V74, A76, L78, C85, L86, V93, I96, L101
376 Complement receptor type 2 P20023 I47, I58, L63, C65, V96, Y108, V114, V130, C132
377 HLA class II P20036 M54, F55, F63, V65, F83, A87, A92, I94, L136, I137, C138, I140, F143, W152, F179, L182, V185, Y192, C194, V196,
histocompatibility antigen, H198
DP alpha 1 chain
378 Myeloid cell surface antigen P20138 V82
CD33
379 Kallikrein-2 (EC 3.4.21.35) P20151 I25, C31, V40, A41, V53, L54, V55, V60, L61, A63, A64, C66, V73, L75, V90, V92, L121, L123, L124, L126, I132, V135,
V136, C152, A154, F165, C173, V174, L176, C184, C198, A199, L217, C219, L223, I226, A241, V242, Y243, V246, I253
380 B-cell receptor CD22 P20273 W24, W35, C39, V40, I42, C44, L53, L76, F94, L95, C102, L117, L119, W128, M129, L134, V136, I145, C161, C167,
Y170, I172, W176, V198, L204, F206, W210, C219, L229, L236, V238, V255, C265, W279, L294, L296, Y307, C309,
L325, V327, Y329, V349, C353, A357, W366, Y394, C396, L413, V415, V422, I426, I432, V438, L440, C442, V451,
W456, L470, I472, V475, W477, C484, A486, C491, L499, V501, Y503, A504, V508, V510, L527, C529, V539, W543,
L556, I561, Y569, C571, I577, V589, Y591, L596, V598, V606, L614, C616, A620, Y627, W629, F630, L644, L646,
Y657, C659, V677, Y678, Y679, I684
381 Integrin alpha-L P20701 F45, I57, V58, L70, C73, L109, A110, C111, C119, C129, Y130, V155, L157, V158, F159, L160, F161, L167, I175, F178,
M179, V182, M183, L186, Y191, F193, A194, A195, V196, F198, F206, F208, Y211, A236, I237, V240, V244, V258,
L259, I260, I261, I262, I273, A276, I279, Y282, I283, I284, I286, F290, L299, F302, A303, F310, F317, L320, L323,
F324, L327, V364, V365, A367, A370, A374, F377, L378, L404, L411, L420, A421, V433, L434, L435, V467, L477, L478,
L479, I480, A482, V494, L510, F521, L528, I531, V539, A540, V541, A543, A550, Y552, I553, F554, L561, I569, I578,
F581, A597, A600, A603, M607, I608
382 Integrin alpha-X P20702 F30, F37, V49, V50, V51, A53, L66, C69, A87, M90, L92, L105, L106, A107, C108, C126, F127, I152, V153, F154, L155,
I156, M170, F173, V174, V177, F188, L190, M191, F193, F201, F203, F206, L216, A229, A231, I232, V235, L239, I253,
L254, I255, V256, I257, V272, I273, A276, I282, A285, I286, V288, A291, F292, L301, I304, A305, F314, V316, F319,
L322, L329, I333, F334, A352, V366, L367, A369, A379, I391, M400, L405, A412, L420, V421, L422, A424, A433,
V434, I435, F436, V465, V467, L475, V476, L477, I478, A480, V492, V494, C495, L510, F521, L528, V531, V539,
V540, I541, A543, A552, V553, Y554, L555, F556, I572, A573, L581, F584, L602, A603, V604, A606, V610, L613, V618,
L619, I632, V650, I658, L671, V675, L681, A690, F692, L700, F715, L717, L719, I730, L732, L734, L749, L765, L793,
V795, L801, A803, V805, V807, I819, F821, H823, C863, A880, F882, A888, L894, L896, A898, V924, A951, H953,
Y955, V957, L965, V967, I969, F971, V973, L977, V982, W983, I1014, L1020, A1025, C1027, C1032, F1037, V1039,
L1043, F1045, L1047, L1051, W1055, I1059, V1064, V1066, A1070, I1072, L1097
383 B-cell lymphoma 3 protein P20749 L139, V143, V151, F158, L176, H177, A179, V180, V188, L191, A208, H210, A212, C213, C220, L221, A223, L224,
A245, L246, H247, A249, V250, V258, L260, L261, L280, I281, A283, V284, M291, V292, L294, L295, A312, L313,
A316, V325, L328, V354
384 Calpain-3 (EC 3.4.22.54) P20807 L138, L145, L189, F200, A210, L212, Y216, A218, F239, A335, V363, F404, F658, A662, I668, L673, L677, V681,
C697, M700, M704, L712, F717, L720, I724, F731, I742, M747, A750, V751, A754, Y763, I777, F779, F782, I783,
C785, F786, L815
385 Collagen alpha-1 P20849 L59, V65, A86, F113, L114, F117, M119, W128, I130, W131, I133, I144, I146, V153, F155, F169, I183, M184, I185,
V187, A192, L194, A218, V219, V231, L235, M238, I240
386 Nebulin P20929 A6617, F6631, I6637
387 N(4)-(beta-N- P20933 I91, L105, I108, A111, I112, V114, A115, V118, A132, A136, A243, A253, A254, A256, L263, A272, V273, A285, C286,
acetylglucosaminyl)-L- I290, I293, F300, A303, V304, C306, C317
asparaginase (EC 3.5.1.26)
388 Filamin-A P21333 F49, C53, L57, I64, L67, L71, L77, I78, L80, L81, V107, V109, A110, L111, F113, L114, I129, I137, L138, L140, I141,
L144, I145, I150, L172, I176, L180, I185, F188, W192, A197, L198, A200, L201, V202, A206, C210, A225, A228, M229,
A232, L236, I238, V241, I242, I247, V257, M258, Y260, L261, F264, A284, A302, V306, A311, V318, V344, H354, V356,
V358, F360, I365, V372, V495, A501, V505, A510, V519, F540, Y542, Y550, V552, I554, I561, V568, A595, F597,
V598, V599, V633, Y635, Y643, A644, V647, I654, A661, V675, V697, H743, A745, V747, V761, V1070, F1088, I1090,
A1095, V1124, Y1126, Y1134, I1136, I1138, I1145, A1152, V1154, V1163, C1165, F1181, V1183, A1188, I1197,
I1219, Y1221, Y1229, V1231, I1233, Y1235, L1247, V1258, V1270, F1278, V1280, V1297, Y1317, V1319, Y1321,
H1329, V1331, V1333, V1347, V1358, F1376, V1378, A1383, V1412, Y1414, Y1422, L1424, V1426, V1433, V1440,
V1451, V1463, V1473, A1478, V1487, V1509, I1521, V1523, Y1525, V1530, V1537, V1539, V1548, V1560, A1562,
F1568, I1570, A1572, A1575, I1584, V1606, Y1608, Y1616, I1618, I1620, Y1622, I1627, V1634, A1636, A1642, C1645,
I1672, V1674, A1679, V1684, V1688, I1710, A1714, Y1720, I1722, V1724, V1731, V1738, A1740, F1791, I1795, I1799,
V1808, V1828, V1830, H1840, M1842, I1844, I1851, L1856, F1858, V1860, V1868, A1870, L1875, F1886, V1888,
I1902, V1922, Y1924, Y1932, I1934, V1936, V1943, F1948, A1950, V1952, V1987, I2009, F2011, H2019, V2021,
V2023, I2039, A2047, V2050, L2057, F2068, I2070, A2075, L2080, L2082, I2084, V2104, Y2106, Y2114, I2116, I2118,
F2120, V2125, V2132, V2134, A2176, V2178, Y2198, I2200, H2210, V2212, V2214, V2230, A2238, V2241, A2257,
F2259, I2261, A2268, I2273, V2275, V2295, Y2297, V2299, Y2305, V2307, V2309, F2311, I2316, V2323, V2325,
A2326, A2332, L2335, L2345, V2355, L2357, A2360, I2364, V2368, V2390, Y2400, I2402, V2404, F2406, I2418,
V2432, L2439, F2450, V2452, A2457, V2485, Y2487, A2491, Y2495, I2497, I2499, Y2501, I2507, A2514, A2557,
V2560, A2570, V2580, C2582, V2616, Y2618, L2620, L2628, V2630, W2632, I2637, V2644
389 Neurofibromin P21359 I1592, I1605, F1606, Y1607, V1609, F1613, L1623, V1642, A1670, Y1680, L1715, I1719, A1743, I1755, A1761,
V1762, V1772, A1785, I1788, F1799, L1801, I1803, F1812, C1817, I1820, I1824
390 Phosphatidylcholine P21439 A64, M81, L109, M113, Y120, V127, A131, F137, A141, A142, I146, I149, F153, F154, A156, I157, L158, I162, L173,
translocator ABCB4 L177, I181, I184, I188, A200, V208, L216, I220, A235, A252, A256, A259, A262, V266, A268, F269, Y279, L283, A286,
A294, I303, A304, A310, A313, A315, F316, M334, V336, F337, I340, A350, A360, A364, I367, I371, I377, L394, V399,
L412, L415, V419, V425, A426, L427, V428, C433, L441, I442, I453, I460, F463, V465, L468, I472, V475, L481, F482,
I486, I490, I502, V506, A509, A511, I515, V526, I541, A542, I543, A544, A546, I553, L555, L556, A559, V571, A574,
L575, A578, I585, I587, V594, I600, A601, F603, L617, Y624, V700, C717, A718, I735, I736, I753, I757, F758, L761,
A779, L783, L787, A791, F792, M795, L796, L817, A821, V824, A827, A833, A840, L856, A896, A899, I900, I903,
V906, F915, A934, C955, A960, L975, V976, F982, A1000, A1004, H1006, L1007, I1034, F1036, V1039, F1041, L1052,
L1055, V1059, L1065, A1066, L1067, V1068, V1078, V1079, L1081, L1082, V1093, A1107, L1110, V1112, L1115,
L1119, V1122, F1129, A1134, I1137, I1151, A1154, A1155, A1158, I1160, Y1171, V1175, A1191, I1192, A1193,
L1196, L1204, L1205, V1220, A1223, C1233, I1234, I1236, I1243, I1249, V1250, V1251, L1266, Y1273
391 Tumor necrosis factor alpha- P21580 L10, A18, I21, I37, H38, H39, F40, M43, H44, L48, F51, I64, A67, L68, L77, L83, A94, L104, M105, H106, A107, Y111,
induced protein 3 M112, W113, V115, L122, A125, L126, F138, A175, H195, I196, F197, V198, L199, C200, I202, L203, I207, I208,
V209, V229, I232, Y233, L234, I248, V249, L250, V258, L260, V261, A272, V273, V288, H289, F290, L291, L302, L307,
V314, I325, A327, A328, L330, I339, L341, Y345, V349, C404, C624, C779
392 Kit ligand (Mast cell growth P21583 V40, L43, L55, I70, M73, V74, L77, L81, I100, I101, L104, I107, V108, F140, F141, F144
factor)
393 Ephrin type-A receptor 1 P21709 L81, A92, V95, H96, V97, L99, F101, V103, F122, L124, V148, L181, L183, A184, F185, A190, V192, L194, V197,
V199
394 Fibroblast growth factor 7 P21781 L69, C71, L77, I79, V85, M98, I100, V108, I110, L119, A120, M121, C137, F139, Y151, V165, A166, L167, A186,
F188
395 Fibroblast growth factor P21802 M162, V169, V175, F177, C179, A181, F198, L216, M218, V221, Y229, C231, V233, Y244, L246, F276, C278, W290,
receptor 2 I324, C342, A344, A355, L357
396 Ryanodine receptor 1 P21817 L13, V19, V20, L21, C23, A25, L34, C35, L36, A37, A38, I63, C64, F66, L68, L77, L100, Y102, A105, I106, L108, H110,
L117, A131, V134, L136, C145, W147, M149, V162, I168, L170, L179, V190, A192, W199, M201, V213, L219, L221,
H223, C229, L230, I232, V244, Y246, V251, A255, L258, W259, L261, L273, L279, V281, H283, V284, Y289, L290,
A291, V299, V300, A306, F313, F315, I338, C345, V347, L356, A375, L387, L389, A399, A400, M402, I403, Y410,
F413, L435, V440, L444, L447, I448, F451, L470, L476, F477, M482, V486, C489, I490, L493, F502, A506, I517, V518,
L521, L524, L528, W685, A686, V706, C745, I754, V779, V780, A874, F909, V984, A988, H992, L1038, V1042, A1093,
V1101, W1103, A1104, L1114, A1120, V1122, F1123, V1148, C1150, I1152, I1159, F1161, I1181, V1190, A1449,
W1451, V1452, L1465, V1471, V1473, M1475, I1515, M1526, F1528, A1550, F2754, A2759, Y2761, H2763, A2767,
L2813, A2815, M2816, L2862, M2874, L2878, A2879, A2923, L2926, L2927, L2930
397 Receptor tyrosine-protein P21860 L52, Y53, C56, V58, V59, L63, I65, L77, I80, V83, V87, L88, V89, A90, F94, L97, L99, L102, V104, V105, A116, I117,
kinase erbB-3 (EC 2.7.10.1) F118, V119, L121, A130, L131, L134, L136, L139, I142, V147, I149, L155, M158, I161, I166, V167, C190, C194, W195,
C231, A232, A245, C255, C259, V295, V296, C331, V343, I348, F351, C354, I357, L361, F363, I376, L384, F387, V390,
I393, L397, I399, F409, V411, F412, L415, I418, F428, L430, I432, V438, L441, F443, L446, I449, I454, I456, L462,
C463, H465, V473, L474, C493, C504, C509, W510, C529, C533, C552
398 Succinate dehydrogenase P21912 F42, I44, V63, V72, A75, L76, I79, L87, C101, M103, L111, A112, I127, F146, L183, A190, C191, Y199, Y206, A210,
[ubiquinone] iron-sulfur V211, L212, A215, L234, L240, A262, I263, I266
subunit, mitochondrial (EC
1.3.5.1)
399 Tenascin-X P22105 C435, C466, L3669, L3671, A3679, F3683, L3685, A3716, L3718, L3729, L3731, A3859, L3861, Y3873, V3875,
V3877, L3898, A3909, V3911, A3947, L3949, Y3961, L3963, L3977, L3986, Y3995, A3997, L3999, A4001
400 Cadherin-3 P22223 V116, L131, I141, V157, F158, L167, L169, L173, L183, A187, I201, I203, V224, V237, A254, M269, I279, V281, Y294,
L296, I298, A300, A312, A314, V316, I318, L349, L390, L396, L406, V408, V410, A425, I427, V429, Y462, V495, L501,
Y514, V516, V518, A520, L534, L536, I553, L565, V602, L604, V617, L619, L621, I633, A635
401 Interleukin-10 P22301 L41, L44, A47, V51, F55, L66, L70, A82, L83, M86, Y90, V94, A98, V109, L112, L116, C126, L130, V139, A157, M158,
F161, F164, I165, I168
402 C-C motif chemokine 1 P22362 I47, L62, F64, A74, V81
403 Ectonucleotide P22413 C164, C166, C170, A392, I507, I632, F638, L826
pyrophosphatase/phosphodi-
esterase family member 1
404 Potassium voltage-gated P22460 I124, I126, L138, L146, F165, F172, I175, Y179, V191, F196, I200, Y203, I260, V445, A451, V452, A455, A470, A474,
channel subfamily A C500
member 5
405 Protein-glutamine gamma- P22735 V709, I711, L721, V724, F726, L728, I744
glutamyltransferase K (EC
2.3.2.13)
406 Carbonic anhydrase 4 (EC P22748 Y25, I54, I56, Y75, W81, V83, V90, M92, L94, I100, Y109, A111, L114, L116, W118, H128, M137, M139, H140, I141,
4.2.1.1) H143, A164, L166, A167, F168, L169, V170, F180, L187, I190, Y217, C229, V233, V237, F238, I242, L244, F252,
L256, M266
407 Peptidyl-prolyl cis-trans P23284 V42, V44, V46, Y47, F48, L50, I52, V60, I61, F62, L64, F65, V69, V73, F76, A78, L79, A80, F86, Y88, F93, V96, I97,
isomerase B M101, I102, I118, F123, L130, H132, W137, V138, M140, F152, F153, I154, V167, V168, F169, V172, V178, V179, V182,
L194, V197, I198, I199, I205
408 Glycine receptor subunit P23415 V65, V67, C69, I71, I73, Y86, V88, I90, L92, W96, L101, L111, L146, I148, V154, I160, L162, L164, C166, L170, F173,
alpha-1 C180, M182, L184, L194, F196, C237, I238, A240, F242, L244
409 Receptor-type tyrosine- P23468 A41, F43, C45, W57, F69, V81, L82, I84, L87, Y96, C98, A100, L113, V115, A143, M145, C147, A148, A149, W159,
protein phosphatase delta L192, I194, Y205, C207, A209, A221, L223, I255, C257, A259, V267, W269, V294, C302, A304, A315, I317, I339,
L341, I356, V373, V380, F391, V393, V394, A395, I434, V436, V453, V463, I479, V490, V492, A494, I532, L534, Y547,
L549, I564, L575, F583, L585, A586, A587, I626, V628, I647, A651, L674, I685, V687, A689, L937, L956, L981, V992,
V994, A996
410 Tumor necrosis factor ligand P23510 V64, F66, M86, V93, I95, C97, Y101, I103, L105, V113, I115, L117, V135, V149, L151, L170, L172
superfamily member 4
411 Brain-derived neurotrophic P23560 C141, A150, V164, V166, V170, C196, A217, I226, I231, I233
factor
412 Follicle-stimulating hormone P23945 F30, C32, V37, A48, L51, F53, L58, I61, F66, F69, L72, I75, I77, L83, I86, V90, F91, L94, L97, I100, I102, A105, L108,
receptor L109, A115, F116, L119, L122, L125, I127, I132, L135, V138, I141, V147, L149, I151, I157, I160, F165, L168, V173,
L175, L177, I182, A189, F190, L195, L198, L200, L206, V213, L223, I225, I230, L238, L241, L244, A246, L261, A267
413 Sodium-dependent P23975 L95, L109, A145, I156, L238, F272, L284, I291, A305, I309, L319, V325, Y367, V379, L386, V387, F388, I389, L390,
noradrenaline transporter Y391, A394, A405, I428, F459, I466, L469, L472, A477, L486, I490, F495, F540, I549, A554, W556, V569
414 Protein kinase C eta type P24723 V360, M370, L371, A372, V383, V390, I406, L407, A410, F415, L416, L429, F430, F431, V432, L441, A456, Y459,
(EC 2.7.11.13) A460, A461, I463, I464, A466, L467, L470, I475, Y477, V485, L487, C493, L495, F498, W537, M540, L543, L544,
M547, A581, I584, L585, F588, I608, F613, F614, V641, F644, F671, F674
415 Deoxyribonuclease-1 (EC P24855 I25, A26, A27, F28, I30, F33, M38, V44, I47, V48, I50, L51, Y54, I56, A57, L58, V59, V62, A69, V70, L73, L77, Y102,
3.1.21.1) L103, F104, V105, V111, F131, I137, V138, F140, V147, F150, A151, I152, V153, L155, A157, A162, I166, L169, V172,
V176, V185, M186, L187, M188, F191, A193, I206, L208, I218, C231, A232, I236, V237, V238, A239, L243, A246,
F257, A268, I271, V277, V279, L281
416 C-X-C chemokine receptor P25024 L37, C110, C187, V190
type 1
417 C-X-C chemokine receptor P25025 L155
type 2
418 Adenomatous polyposis coli P25054 L137, L204, I224, C344, L356, A383, A386, L387, I391, V406, L407, L410, I413, Y416, C417, C420, I446, V450, L453,
protein A465, M466, L469, L472, A474, I475, A476, L478, L479, V481, L497, A501, A504, L505, L508, L519, C520, C525,
M526, L529, L540, I544, A545, V547, L548, L551, L563, V569, L572, M573, C575, A576, V588, L589, A591, L592,
L595, I606, A612, L613, L616, I631, I638, L639, V642, I646, L656, C661, L665, I676, A680, C681, L684, L687,
A703, L707, I718, A725, L729
419 Myelin protein P0 P25189 L48, C50, F64, W66, F80, F95, I112, I114, F125, C127, L144
420 Tumor necrosis factor P25445 C63, C73, C85, C119
receptor superfamily
member 6
421 Integrin beta-7 P26010 C54, I55, C61, W63, C64, L86, L123, A124, V128, V130, L132, V142, F144, V152, L154, Y155, Y156, L157, M158,
L160, M164, I191, F193, F196, V197, F204, V205, C216, F229, F242, V246, V251, A264, I265, L266, A268, A269,
C271, I275, L283, L284, V285, F286, Y327, L337, A340, I345, A347, V348, Y356, A367, V378, A385, L395, Y408,
C428, V431, V437, F439, V441, L443, A445, L455, L457, A459, L466, V468, L470
422 Hemagglutinin [Cleaved P26136 I29, C30, L31, A35, V42, V52, L58, V59, L67, C68, L74, C80, L82, I83, A86, L87, C92, L95, V102, F103, I104, V110,
into: Hemagglutinin HA1 C113, Y114, F116, Y121, L124, L128, A129, L134, F141, A154, C155, F163, F164, L167, L170, I181, Y195, W197,
chain; Hemagglutinin HA2 V199, H200, H201, Y212, V219, V221, I247, I249, Y250, L253, V254, I260, F262, L268, I269, A270, Y275, I292,
chain]/strain C299, L300, I306, V327, L334, A335, A352, W361, Y369, A391, A443, L465, L473, C484, F485, I487, H489, C491,
A/Mallard/Astrakhan/263/ C495, I496, I499, A513
1982 H14N5 (Influenza A
virus (strain
A/Mallard/Gurjev/263/1982
H14N5))
423 Hepatocyte growth factor- P26927 C157, C169, Y199, W215, C240, W250, C251, Y252, C263, L265, C391, W394, H400, L414, C419, C431, C443, V484,
like protein W494, V496, L498, L511, I517, L518, A520, V536, L538, V555, L569, V570, L571, L572, V584, C602, I604, A605,
L624, C632, M645, C646, L665, A666, C667, L675, I678, I679, V697, I704
424 Serum P27169 L28, I48, A63, F64, I65, I85, M88, L129, L130, V131, V132, V141, L143, F144, L153, I159, L167, I170, F178, Y179,
paraoxonase/arylesterase 1 G180, V205, F220, A223, I226, V235, I237, A238, I245, V247, L267, V268, L280, V282, C284, H285, V304, I307, A322,
L328, V333, A334, L341, L342, I343, A350, L351, C353
425 Dipeptidyl peptidase 4 (EC P27487 Y43, Y68, L69, A81, L90, I114, L116, A130, Y132, I134, L142, L164, A165, V167, I172, V174, I198, W201, V202, Y203,
3.4.14.5) V207, A213, L223, A224, Y225, A226, F228, I236, Y238, Y241, A259, A261, F268, V270, V271, I287, M293, Y299,
L300, C301, V303, I311, L313, W315, V324, M325, I327, C328, C339, L340, I346, W353, V354, F371, H383, I384,
C385, I389, V404, L415, Y416, Y417, I418, L431, I434, V442, L445, C447, C454, Y468, L470, C472, L482, L500, V507,
L514, L519, M528, L530, L542, L543, L544, V546, A548, C551, A555, L567, A568, I573, I574, V575, A576, F578,
M591, A593, I594, L598, V603, I607, A609, A610, F613, V619, I624, A625, I626, Y631, Y634, V635, M638, V639, L640,
C649, I651, A652, V653, A654, V656, W659, Y661, Y662, V665, Y666, Y670, M671, Y683, V688, A692, F695, Y700,
L701, L702, I703, H704, V711, I719, L723, V724, V726, F730, Y735, H740, I742, I751, M755, F758, I759, C762, F763
426 Genome polyprotein P27909 L29, M48, M126, V128, C148, C167, C180, C182, V189, Y191, A251, A255, M281, C283, V301, V303, V304, L305,
[Cleaved into: Capsid C310, V311, M314, A315, L321, I323, L325, V330, L339, C340, I341, A360, C385, L394, C396, A397, F399, L405,
protein C/strain Brazil/97- V410, L415, Y417, V419, V421, I444, I453, L455, L461, L463, C465, L471, V477, L478, L479, M481, V488, F493, L517,
11/1997 (DENV-1) V518, L544, H562, L563, C565, L567, M569, L572, C582, F586, V592, V600, V602, V604, Y606, C613, I615, I632, V638,
I647, I658, V660, W671, I963, I993, L1396, L1398, I1497, Y1498, I1500, V1513, V1515, F1516, V1520, F1521, H1522,
M1524, L1533, M1534, V1547, L1551, I1552, Y1554, W1558, F1560, V1570, V1572, I1573, A1574, V1575, V1584,
F1591, A1600, I1601, I1614, V1615, V1622, L1624, Y1625, V1630, Y1636, V1637, A1643, L1680, I1683, V1684,
A1687, L1695, I1696, L1697, A1698, V1703, A1704, M1707, A1708, L1711, V1733, L1735, M1736, H1738, F1741,
Y1754, M1756, I1757, I1758, M1759, A1762, I1770, A1771, A1772, I1776, A1785, A1786, A1787, I1788, F1789,
M1790, I1827, V1835, W1836, F1837, V1838, I1847, A1848, C1850, L1851, I1859, L1861, F1866, W1878, Y1880, V1881,
V1882, A1891, V1898, I1899, V1917, V1925, A1928, A1930, A1931, I1937, Y1948, V1949, L1955, A1962, A1967,
L1970, L1971, I1974, L1984, F2009, V2010, L2012, L2018, W2021, L2022, V2026, A2027, W2038, C2039, V2048,
I2057, L2067, A2074, F2086, F2089, A2090, W2506, Y2521, I2526, V2529, L2538, A2547, V2548, A2553, L2555,
F2558, V2559, V2564, V2570, I2571, L2573, C2575, C2584, A2585, V2590, V2593, Y2596, V2625, C2633, L2636,
L2637, C2638, I2649, L2655, V2657, L2658, V2661, W2664, L2665, C2671, I2672, I2674, L2675, Y2678, V2682, L2686,
M2689, M2696, L2697, H2708, M2710, Y2711, W2712, V2713, I2720, V2724, M2730, L2731, I2769, I2776, V2817,
L2820, W2824, I2865, M2866, A2870, L2873, V2904, A2914, A2917, F2923, C2939, C2942, V2943, Y2944, M2969,
L2971, A2973, L2976, A2980, F2983, M2984, W2989, F2990, V2999, L3007, Y3009, L3011, I3014, I3017, M3022,
I3034, A3057, I3060, Y3065, V3069, V3070, V3072, V3081, V3084, I3085, L3101, F3104, M3107, V3109, L3111,
I3112, M3115, L3126, V3135, L3139, L3147, M3150, A3151, I3152, V3158, V3159, F3166, A3169, L3170, A3172,
L3173, M3176, V3198, F3200, F3205, I3216, V3217, V3218, C3220, V3227, A3230, A3236, A3244, A3251, W3254, L3256,
F3259, H3260, L3264, A3267, A3268, A3270, I3271, A3274, V3275, V3277, H3290, L3302, W3305, V3308, W3309,
W3315, V3328, L3331, A3352, I3355, I3359, L3365, L3372, M3375, M3378
427 Interleukin-1 receptor type 2 P27930 V46, L48, W69, A92, L93, L95, A98, C108, I121, L150, W169, L192, V194, Y205, C207, I220, I224, C258, V260, L262,
A276, I281, V328
428 Genome polyprotein P27958 V194, V203, C207, C226, C229, V230, C238, W239, V240, L258, I262, L265, A269, C272, L275, C281, L286, F291,
[Cleaved into: Core protein W353, V355, A426, L427, W437, F442, C459, F465, C486, C494, A499, V502, C503, V506, C508, F509, F537, L539,
p21/genotype 1a (isolate H) W549, C552, W554, C564, A566, C569, C581, C585, F586, A592, Y594, C597, I603, C607, M608, V609, Y611, V629,
(HCV) M631, A642, A643, C644, C652, L665, V674, A684, I690, L692, V699, Y701, V720, L724, L725, L754, C922, V949,
L964, A1004, I1061, L1070, A1071, C1073, I1074, V1077, C1078, W1079, V1081, A1085, V1097, L1108, V1109, L1120,
L1130, L1132, I1140, V1142, I1158, L1161, L1169, C1171, A1176, V1177, L1179, F1180, A1190, A1192, V1193,
F1195, I1196, V1198, L1201, L1228, V1251, L1252, V1253, L1254, M1268, I1291, Y1293, Y1296, A1301, I1312,
I1314, C1315, C1318, I1326, I1329, V1332, A1336, L1343, V1344, V1345, L1346, A1347, I1362, I1373, F1375, I1380,
V1384, I1385, L1391, I1392, F1393, C1394, C1400, L1403, L1407, I1412, V1432, V1433, V1434, V1435, L1440, F1444,
F1448, V1451, I1452, F1470, A1481, Y1499, L1517, C1518, C1520, Y1521, A1526, Y1528, L1539, Y1542, L1555,
F1557, W1558, V1561, L1565, I1568, F1572, L1586, V1587, A1588, A1591, C1594, A1599, L1611, H1619, L1624,
L1625, L1628, I1641, I1645, V2128, L2441, L2450, L2451, V2457, Y2458, A2465, Y2484, V2487, V2491, A2493, A2494,
A2495, V2498, A2500, A2508, C2509, Y2523, A2525, V2528, A2532, A2535, I2539, L2546, L2547, I2558, C2566,
A2577, L2579, V2581, L2585, V2587, V2589, C2590, A2594, L2595, V2598, V2599, L2602, A2605, V2606, Y2611,
V2621, L2624, A2627, M2635, L2637, Y2639, V2648, I2653, I2659, Y2660, C2662, C2663, A2669, A2672, I2673,
L2676, L2680, Y2681, L2686, C2694, C2699, A2701, V2704, L2705, C2709, L2713, A2719, A2721, A2722, C2723,
A2726, L2728, M2733, L2734, V2735, L2740, V2741, V2742, I2743, C2744, A2754, L2756, F2759, A2762, M2763,
Y2766, A2768, I2783, V2790, A2793, Y2802, L2804, L2812, A2813, A2815, A2816, L2829, I2832, I2833, A2836,
L2839, W2840, A2841, I2844, L2845, M2846, H2848, F2849, F2850, L2859, A2862, C2865, I2867, A2870, C2871,
Y2872, I2874, L2877, L2879, I2882, I2883, L2886, A2891, F2892, V2905, A2906, C2908, L2909, L2912, V2914,
A2919, W2920, A2924, V2927, L2931, L2932, A2938, A2939, C2941, L2945, F2946, A2949, A2961, A2962, F2971,
A2973, Y2975, I2980
429 Proteasome subunit beta P28062 L76, A77, F78, F80, V84, I85, A86, A87, V88, A92, A94, V106, I107, L113, L114, M117, C124, L131, C135, L137, I146,
type-8 (EC 3.4.25.1) V148, A150, A151, L155, M159, M169, M172, I173, C174, L183, V186, A207, M211, A224, L227, A231, I232, A233,
A235, V245, V246, M248, Y249, H250, M251
430 HLA class II P28068 L51, M61, A73, L90, C97, V117, V119, M132, L133, A134, C135, V137, F140, W149, C192, V194
histocompatibility antigen,
DM beta chain
431 Gamma-aminobutyric acid P28472 V63, M65, I67, I69, Y82, L84, M86, W92, L97, I141, V149, A159, L165, C175, L177, I179, I189, A199, L233, L235,
receptor subunit beta-3 F237
432 Mitogen-activated protein P28482 A9, V14, F19, V21, Y25, I31, A35, Y36, M38, C40, A42, V49, V51, A52, I53, I56, C65, L69, I72, I74, L75, I83, I84, I86,
kinase 1 I89, I95, M98, V101, Y102, I103, V104, L112, L115, L116, L121, H125, I126, C127, F129, L130, I133, L134, L137,
I140, H141, A143, V145, L146, H147, L150, L155, L156, L157, L163, I165, F168, L170, A171, L184, A189, W192, Y193,
A195, I198, M199, L200, Y205, I209, I211, W212, V214, C216, I217, L218, A219, M221, L222, I227, F228, L234, L237,
I240, L241, L244, L252, I255, A260, L264, L267, F279, A286, L287, L289, L290, M293, L294, A307, L308, L313, F329,
M333, L335, L338, L343, I347
433 Granulins (Proepithelin) P28799 C133, C157, C215, C239, C290, C314, C372, C396
(PEPI) [Cleaved into:
Acrogranin (Glycoprotein of
88 Kda) (GP88)
(Glycoprotein 88)
(Progranulin); Paragranulin;
Granulin-1 (Granulin G);
Granulin-2 (Granulin F);
Granulin-3 (Granulin B);
Granulin-4 (Granulin A);
Granulin-5 (Granulin C);
Granulin-6 (Granulin D);
Granulin-7 (Granulin E)]
434 ADP-ribosyl cyclase/cyclic P28907 F59, V63, C67, Y70, M77, V85, F89, A92, F93, I101, Y106, L109, M110, C119, I122, L123, L124, A132, F135, L145,
ADP-ribose hydrolase 1 (EC L149, L150, L153, A154, W159, C160, V187, F188, V192, A197, A199, A200, V204, V206, M207, L208, I215, F216,
3.2.2.6) F222, V225, V227, L230, V235, L238, A240, V242, L253, I259, L262, I266
435 Tumor necrosis factor P28908 C44, C45, C48, C58, C65, C69, Y74, C81, A83, C84, V85, C87, L92, V93, C98, V105, C106, C108, F113, C114, C122,
receptor superfamily A123, C125, C131, I136, V137, C233, C240, C244, Y249, L250, C256, C259, V260, C262, L267, V268, C273, W275,
member 8 C281, C283, C289, C297, A298, C300, C306, V311
436 Gap junction beta-2 protein P29033 W44, F51, C60, C64, H73, C169, A171, C180
437 Neuroendocrine convertase P29120 C319, A393, V411, A511, L525
1
438 Amyloid beta A4 protein P29216 C49, C53
439 Ephrin type-A receptor 3 P29320 L33, Y68, V70, L82, V87, A92, I95, Y96, V97, L99, F101, L103, V112, F120, L122, I146, M155, V171, F179, Y180, L181,
(EC 2.7.10.1) A182, F183, A188, V190, A191, L192, V195, V197, A436
440 Ephrin type-B receptor 2 P29323 W43, V61, W72, L73, I78, A83, I86, V88, M90, F92, V94, V103, F111, L113, I141, V150, I159, F166, V169, F174, Y175,
(EC 2.7.10.1) L176, A177, F178, L187, V190, V192, A435
441 Collagen alpha-5 P29400 I1464, L1490, Y1491, L1503, Y1537, W1538, L1539, I1561, C1564, A1565, V1566, C1567, A1569, F1599, H1602,
C1620, F1629, I1630, C1632, C1638, C1678, V1680, C1681, M1682
442 Interleukin-12 subunit alpha P29459 V48, M51, A55, I105, C123, L131, M141, M159, I163, C196, L199, I209
443 Interleukin-12 subunit beta P29460 V30, V32, V33, V46, I58, W60, V79, A85, C90, L102, L104, I116, A133, F140, C142, W144, V191, C193, I208, V210,
V212, A214, Y220, Y223, I229, I233, V252, V254, L271, F273, C274, V275, V277, A304, I306, V308, A310
444 Protein PML P29590 C57, C66, L73, H74, L76, C129, C140, C148
445 Non-receptor tyrosine- P29597 L28, V30, A53, V56, I60, A61, V64, L73, L76, A81, L91, L101, F103, F109, Y151, L152, F153, F160, A165, L184, M186,
protein kinase TYK2 (EC A187, L191, H193, C214, I215, F219, Y259, L260, L263, A267, V277, L280, L283, V316, V318, I324, C378, F380,
2.7.10.2) V393, I395, C402, L403, L405, L407, A413, F416, V417, L419, V420, Y423, L426, V438, H452, Y471, L472, L483, L485,
V487, I507, V526, L529, I563, V639, L641, L644, F655, A659, V676, C677, I684, M685, V686, L695, L699, V714,
A715, L718, A719, A721, L722, L725, V735, I740, L742, I755, L757, V762, V773, I776, A780, W798, F800, A802, L804,
L805, I807, C838, L841, L844, C848, F859, I862, L866, L913, V927, V929, A934, W944, I948, L951, H958, I959, I960,
C966, L974, L976, V977, L986, L990, L1000, L1001, F1003, A1004, I1007, C1008, M1011, L1014, I1020, H1021, L1024,
A1025, A1026, V1029, L1031, V1037, I1039, F1042, L1044, A1045, A1069, C1072, F1078, V1084, F1087, V1089, L1091,
Y1092, L1094, L1124, L1127, L1128, L1134, C1140, V1144, M1148, C1151, W1152, L1165, L1169
446 CD40 ligand P29965 A124, V126, L138, V153, L161, V163, Y169, I171, A173, V175, F177, F189, A191, L193, L231, A235, V237, V239,
V241, F256, L258
447 Peroxiredoxin-5, P30044 V67, V76, L78, F82, V88, L89, F90, V92, F96, C100, H104, L105, F108, A112, L115, A117, V123, A124, C125, L126,
mitochondrial (EC V128, A131, W137, A140, A143, L150, A151, F157, L178, F181, M183, V184, V185, V190, A207, I210
1.11.1.15)
448 T-cell differentiation antigen P30203 V58, V60, A78, A79, A81, V82, C83, A126, A151, V153, A171, V174, M176, V185, C186, A195, V197, V198, C199,
CD6 A255, A257, V278, V280, F282, V289, C290, A299, V301, L302, C303, C308, M326, Y328, L337, A355, V358, C360
449 Lens fiber major intrinsic P30301 A12, A15, A19, Y23, V24, L28, L32, V44, A45, F48, A51, V67, A70, V71, A74, A86, Y89, A97, A101, V112, L116, V127,
protein A130, V142, I145, F146, A161, V164, L168, H172, A181, M183, A186, A190, A192, V203, Y204, I209
450 HLA class I P30460 M29, Y31, A35, F46, V52, F57, V58, F60, A73, W75, I76, Y83, F91, L102, L105, L119, M122, C125, V127, Y140, Y142,
histocompatibility antigen, Y147, I148, L150, L154, W157, A163, A164, V176, A177, L184, C188, V189, L192, Y195, L196, L203, V213, A223,
B-8 alpha chain L225, C227, A229, F232, Y233, L239, W241, A269, A270, V271, V272, V273, Y281, C283, V285, H287
451 Tyrosine-protein kinase P30530 L54, C56, L58, V98, L102, C117, V119, V133, C160, W173, F203, C205, A207, A219, I221
receptor UFO (EC 2.7.10.1)
452 Type-1 angiotensin II P30556 I27, C101
receptor
453 Fibroblast growth factor 9 P31371 L66, C68, L74, I76, I94, L95, V105, I107, L116, M118, C134, F136, Y148, V164, A165, L166, F184, F187, V197, L200
454 Cytokine receptor common P31785 C62, V64, M70, C72, W74, L85, L87, C102, L106, C115, L117, L124, F128, V129, V130, L132, L146, L148, V152,
subunit gamma L162, L165, L170, L172, W174, L183, H185, V187, F221, V223, F227, A234
455 Low affinity P31994 A50, L62, V67, L69, W84, A103, Y111, C113, L126, L129, L133, V134, L135, L140, F142, I148, L150, C152, L160,
immunoglobulin gamma Fc V163, F165, F166, F181, A186, Y194, C196, I212, V214
region receptor II-b
456 Low affinity P31995 A50, L62, V67, L69, W84, A103, Y111, C113, L126, L129, L133, V134, L135, L140, F142, I148, L150, C152, L160,
immunoglobulin gamma Fc V163, F165, F166, F181, A186, Y194, C196, I212, V214
region receptor II-c
457 Carcinoembryonic antigen- P31997 L36, A45, V51, L52, L53, V55, Y65, W67, I79, I80, A105, L107, M109, V112, Y120, L122, V124, F138
related cell adhesion
molecule 8
458 Neuronal acetylcholine P32297 A139, L140, A153, I187, L189
receptor subunit alpha-3
459 4-hydroxyphenylpyruvate P32754 V22, F24, A29, A33, M40, F42, V61, I62, I67, V68, F69, L71, I96, F98, C103, V107, A110, V131, A134, L136, H144,
dioxygenase (EC 1.13.11.27) L146, V147, C176, I184, V185, Y200, V217, L224, V228, V229, A230, I236, M238, I240, I252, I267, A268, L269,
I274, A277, I278, L281, Y296, L317, I322, Y331, L332, L333, I335, L346, F347, L348, V350, I351, F368
460 T-lymphocyte activation P33681 A46, L48, C50, I64, W66, V73, L74, L99, I101, I103, Y114, C116, V118, I160, C162, W175, V200, L204, F214, C216,
antigen CD80 I218
461 Surface antigen S/isolate P33795 F36, A66, L83, I210, V238
Human/India/Ind3/1967
(VARV) (Smallpox virus)
462 N-acetylgalactosamine-6- P34059 I33, L34, L35, L36, L37, M38, M41, L46, M62, F69, F72, Y73, A75, A84, A85, L86, L87, L91, F97, A104, I113, I117,
sulfatase (EC 3.1.6.4) L123, L124, L128, I137, V138, W141, L143, H154, W159, H166, V180, Y190, A203, Y209, A213, F216, I217, F226,
F227, L228, Y229, W230, A231, V232, A234, Y240, A241, Y254, A257, V258, I261, I265, I268, L272, V283, F284,
F285, A291, I294, C308, F314, M318, A322, L323, A324, W325, I342, F346, L350, L368, Y384, M391, A392, A393,
A400, H401, V427, I441, F442, A464, I468, L486
463 Neurotrophin-4 P34130 V118, V120, A179, I193
464 Catenin alpha-1 P35221 A128, L141, L150, V157, I161, L164, L173, L187, A191, L198, M207, A208, L221, L229, L243, I244, L248, V252,
I255, A258, A259, F285, L305, I312, A316, M319, I333, A339, V340, L344, L347, L348, M371, L378, L382, A385, V386,
H389, V390, L395, L401, L404, A407, A408, V416, F423, A427, L430, V433, A434, A437, C438, V450, M452, L457,
A459, L460, V464, A468, L471, A480, W491, V497, L498, A501, V502, F511, L512, V514, I519, C526, A529, L530,
L538, A542, I545, A549, V552, V556, V572, L573, L579, V583, F587, A594, F611, A614, V618, I622, I625, F691, L698,
I712, A716, M719, M723, M726, V742, A745, A746, I749, A752, M756, L759, I763, L776, L780, I783, L790, C793,
A815, L818, I819, A821, A822, L825, M826, A828, V829, V833, A839, A896, A902
465 Catenin beta-1 P35222 A149, I153, L160, V168, A171, A172, V175, I188, M194, V195, A197, I198, V199, M202, C213, A215, L218, L221,
L228, I231, I237, A239, L240, V241, V251, L252, A255, I256, L259, L262, L263, A269, V273, L279, M282, L285, F293,
L294, A295, C300, L301, L304, A305, I315, A317, L324, V325, I327, M328, L336, L337, V343, L344, L347, C350, I357,
V358, A360, M363, A365, L366, L368, L370, L377, V378, C381, L382, L385, L388, A391, A392, M398, L401, L402,
L405, V406, L408, L409, V417, C419, A420, A421, I423, L424, L427, V438, I444, L447, V448, V451, A454, I460, A464,
I465, A467, L468, L471, A481, A484, V485, L491, V494, V495, L497, L498, L506, I507, A509, V511, L513, I514, L517,
A518, L519, A522, A525, L527, A532, I533, L536, L539, L540, A543, V564, M566, I569, V570, C573, A576, L577,
L580, A581, V584, I590, I596, L598, F599, V600, L602, L603, I610, V613, A614, A615, V617, L618, L621, A622,
A627, A628, A630, I631, A633, A636, L640, L643, L644, V651, A652, A655, A656, V658, L659, L781
466 Interleukin-13 P35225 L43, L46, I47, L50, C62, V67, M76, Y77, A79, A80, L81, L84, I93, L100, C104, V125, F128, V129, L132, L136
467 Thrombospondin-2 P35442 I600, C619, A639, C707, C715, C720, C756, C779, C815, C838, C876, A882, C912, C932, C948, F959, V965, L967,
L988, I998, A999, V1000, F1005, F1010, V1016, Y1024, A1025, F1027, V1028, F1029, Y1031, F1037, Y1038, V1039,
M1041, A1057, L1065, V1067, V1068, L1078, A1081, L1082, W1083, V1092, L1114, H1116, I1123, V1125, Y1145,
L1150, L1152, F1153, V1154, F1155, V1160, F1162, L1165, Y1167, C1169
468 D(3) dopamine receptor P35462 C103
(Dopamine D3 receptor)
469 Alpha-L-iduronidase (EC P35475 V32, V34, W47, F52, A61, V65, L72, L74, A75, Y76, V77, A79, V88, W92, L93, L94, L96, V97, L114, Y117, L120, L121,
3.2.1.76) F130, L132, M133, A136, F140, F143, V149, W152, L155, V156, L159, A160, Y163, V172, W175, F177, W180, F198,
Y201, Y202, A204, C205, L209, L216, L218, F225, L237, L238, Y258, I259, L261, I272, V279, I283, A300, A314,
V316, Y318, A319, A320, M321, V322, V323, V325, I326, A327, H329, L333, A340, L346, A351, L353, F360, L365, A367,
V371, L381, L382, V386, L387, A389, L393, A394, L396, L401, V418, L421, A422, A436, A437, V438, L439, I440,
Y441, A442, A448, V456, L460, V472, L476, C481, F501, M504, A507, L530, L535, L537, V538, H539, V540, C541,
V551, L564, V565, L566, V573, C577, L578, Y581, I583, L604, V614, Y618, V620, A622
470 Fibrillin-1 [Cleaved into: P35555 C67, C80, C100, C134, C145, C853, C875, A882, I911, C1526, C1534, C1562, C1564, A1569, I1607, L1613, L1616,
Asprosin] C2061, C2083, C2084, C2085, I2110, C2111, C2137, C2164, C2190, C2363, C2364, C2365, W2371, C2378
471 Myosin-9 P35579 V34, A44, A54, V56, L58, M86, L89, A95, V97, L98, L101, Y105, L109, I110, Y111, Y113, F117, C118, V119, V120,
I121, I129, I134, V135, Y138, M146, H149, I150, Y151, I153, A157, M161, I170, L171, C172, A178, V187, I188, Y190,
L191, A192, V194, A195, A214, I217, L218, A220, F221, A224, F235, F238, I239, I241, F243, V250, A252, Y257, L258,
A264, F274, I276, F277, Y278, Y279, L280, L288, L292, L293, F302, L303, I310, F319, A325, M326, M329, L339, L340,
V342, I343, V346, L347, L349, I352, F354, A363, A370, A371, V374, L377, L378, F385, I389, L390, A410, F412, A413,
I414, A416, L417, A418, A420, Y422, M425, F426, L429, V430, I433, L437, I448, I450, L451, F456, F464, L467, C468,
Y471, L479, F480, Y492, I497, F504, L508, C511, I512, L514, I515, I524, L525, L527, L528, F542, V546, F556, F568,
C569, I570, I571, H572, V577, Y579, A581, W584, M589, I596, A597, L600, F607, V608, W612, V646, Y650, L654,
L657, M658, L661, F668, V669, C671, I672, I673, V688, L689, L692, V697, I701, I703, F708, F714, F717, Y721,
I729, A739, C740, M743, I744, V761, F762, F763, V767, L771, I783, F786, M809, M871
472 Alpha-actinin-2 P35609 F44, C48, L70, L75, L76, V100, L114, A119, I122, V123, I134, I138, A142, I143, I146, L157, C161, I173, W180, L184,
L186, C187, A188, L189, I190, L203, I209, I212, A215, M216, A219, A231, V235, A244, I245, M246, Y248, V249,
F252, Y253, A262, L289, A290, I297, L304, A315, M316, L348, L378, A381, L389, A403, F406, A410, H413, A417,
L424, V437, H444, I461, A465, L468, V479, I486, L493, L504, M507, H518, F521, A525, M532, A535, I551, L565, I575,
V582, I593, L607, V614, L625, A646, I649, I667, L678, H683, L695, V707, M717, I720, L727, I731, M798, A839, Y844,
I845, L850, A859, I863, A878
473 Metalloproteinase inhibitor 3 P35625 I40, I42, A44, V46, L60, I64, V79, I82, L104, M113
474 Copper-transporting ATPase P35670 V145, L147, V149, I161, V165, A183, I185, Y187, L197, V201, F206, C271, I279, V285, A297, V299, L311, I315, I363,
2 (EC 3.6.3.54) I365, I377, I381, V401, L413, I417, C490, L492, I494, V503, I506, L510, V516, V519, L520, A528, I530, Y532, I542,
A543, I546, A553, I566, L568, I570, I582, L586, A595, A604, V606, F608, I618, I619, I622, A629, V820, C1079, V1106
475 Myosin-11 P35749 V38, A48, V58, V60, L62, M90, L93, A99, V101, L102, L105, Y109, L113, I114, Y115, Y117, F121, C122, V123, V124,
V125, I133, I138, V139, Y142, M150, H153, I154, Y155, I157, A158, A161, M165, I174, L175, C176, A182, V191, I192,
Y194, L195, A196, V198, A199, A221, I224, L225, A227, F228, A231, F242, F245, I246, I248, F250, V257, A259,
Y264, L265, A271, F281, I283, F284, Y285, Y286, M287, M295, L299, L300, F309, L310, I317, F326, A332, M333,
M336, I346, L347, V349, V350, V353, L354, L356, I359, F361, A370, A377, A378, V381, C382, L384, M385, F392, I396,
L397, A417, F419, A420, V421, A423, L424, A425, A427, Y429, L432, F433, I436, L437, V440, L444, L455, I457, L458,
F463, F471, L474, C475, Y478, L486, F487, Y499, I504, F511, L515, C518, I519, L521, I522, V531, L532, L534, L535,
F549, L553, F563, F575, I577, I578, H579, V584, Y586, A588, W591, M596, V603, L607, F614, V615, W619, V653,
Y657, L661, L664, M665, L668, F675, V676, C678, I679, I680, A692, V695, L696, L699, V704, I708, I710, F715,
F721, F724, Y728, I736, A746, C747, M750, I751, I768, F769, F770, V774, L778, F806, W832, L885
476 Glutaredoxin-1 P35754 V6, I10, V15, V16, V17, F18, I19, C26, A29, I32, L33, I48, I57, L61, V73, F74, I75, L86, L95, L99, A104
477 Vascular endothelial growth P35968 V136, I148, C150, L161, C162, A163, F185, I187, I192, A195, V198, C200, A202, I223, L244, C246, A248, V254, L292,
factor receptor 2 I294, V297, Y305, C307, A309, V322
478 Tyrosine-protein kinase P35991 V219, A221, L233, L235, Y241, A254, I264, A291, V427, I429, I432, F442, M449, L457, V458, Y461, V463, C464,
BTK (EC 2.7.10.2) I470, I472, I473, L482, L486, L498, C502, V505, C506, A508, M509, L512, H519, L522, A523, A524, C527, V529,
V535, V537, F540, V568, I580, W581, F583, V585, L586, M587, W588, I590, I610, A622, I629, M630, C633, W634,
F644, L647, I651
479 Chitinase-3-like protein 1 P36222 L24, V25, C26, Y27, Y28, C41, L46, L50, C51, I54, I55, Y56, F58, A59, L76, Y77, L80, L90, L93, L94, V96, F101, F106,
I109, A110, F119, I120, V123, L127, F132, L135, L137, A138, W139, F150, L153, I154, M157, F161, L172, L173, L174,
A176, A177, L178, A180, I185, I191, I194, L198, F200, I201, I203, H218, H219, L222, A240, V241, M244, L254, V255,
M256, I258, F265, V274, A276, A295, Y297, I299, V316, Y318, A319, W325, V326, Y328, V334, V338, L341, A349,
M350, V351, A353, L354, F359, F370, L372, A375, I376
480 Phosphoglucomutase-1 P36871 L22, V26, Y35, A36, F39, I40, I43, I44, A55, L57, V58, V59, A70, I71, I74, A75, I77, A78, A79, I83, L86, I88, L94, A98,
V99, I103, I106, I112, I113, L114, A116, F127, I129, I147, C160, L163, V165, F184, V186, V192, Y195, L199, L208,
L212, L218, I220, I222, A224, V228, Y232, V233, I236, L237, L241, F257, A269, L272, M276, F283, A285, A286, F287,
M295, I296, L297, V304, V310, A311, V312, I313, I320, F323, F331, A332, M335, L341, A345, F362, L371, L373, C374,
I386, L392, W393, A394, V395, L396, A397, W398, L399, I401, V409, I412, L413, F424, V433, A438, M441, L445,
M449, F454, V468, L490, L492, F494, I500, V501, F502, I514, L516, Y517, I518, I528, L536, L539, A543, L549
481 Receptor-type tyrosine- P36888 L143, L182, C231, A233, L268, I270, C272, A274, C330, F369, F418, A420, A443
protein kinase FLT3 (EC
2.7.10.1)
482 Bone morphogenetic protein P36894 A428, I437, V450, V473, V496, L499, W504, A509, L515, L521, M524, V530
receptor type-1A
483 Activin receptor type-1B P36896 A401, Y410, H423, V446, M469, M472, W477, A482, L488, L494, L497, V503
(EC 2.7.11.30)
484 TGF-beta receptor type-1 P36897 A399, F408, H421, V444, M467, I470, W475, A480, L486, L492, L495, I501
485 Guanine nucleotide-binding P36915 I363, C365, V366, F368, L376, I377, L380
protein-like 1
486 Tumor necrosis factor P36941 C80
receptor superfamily
member 3
487 Pigment epithelium-derived P36955 L54, A55, A57, F61, L65, Y66, V78, L80, V85, A86, A88, L89, L92, A96, I104, L108, Y122, L125, V129, V143, F144,
factor F154, L158, V184, M188, I205, L207, L208, V210, A211, F213, F231, M244, C261, A264, I274, I275, L293, I298, A310,
V314, L317, V325, L329, L337, I346, L353, H358, A360, F362, Y388, L390, F394, I395, F396, V397, L398, L407,
F408, I409, I412
488 Serine/threonine-protein P37023 L405, V418, V441, L464, M467, W472, L483, L489, I492
kinase receptor R3
489 TGF-beta receptor type-2 P37173 C51, C61, C84, V85, A86, V87, V100, C121, F133, C136, C138, I147
490 Electron transfer P38117 V6, L7, V8, V13, A45, V46, A49, V61, I62, A63, V64, I75, A78, L79, A83, I87, H88, V89, V91, A105, V107, L108, L111,
flavoprotein subunit beta A112, L119, V120, A139, A150, L160, V162, A179, V180, V181, A183, A201
491 40S ribosomal protein S19 P39019 V6, F14, L18, A19, F53, A57, A58, A61, L64, V99, A100, V103, L104, V113, L131, A135
492 60S ribosomal protein L3 P39023 A45, F46, L47, I56, V76, I78, V79, M84, V87, I89, V105, C114, M153, I160, V162, A164, H165, M168, A178, V185,
L194, A197, V207, I217, V219, I220, V222, V231, I284, I314, F320, F330, V331, M332, L333, L345, L347, I368, M382
493 Collagen alpha-1 P39060 M1454, V1461, I1467, V1469, L1581, L1583, V1584, A1585, L1586, A1600, C1604, A1608, A1619, F1620, L1621,
L1628, I1631, V1632, I1642, W1654, L1657, V1679, W1685, V1690, W1691, H1692, C1706, W1709, A1720, L1723,
L1728, L1729, C1736, I1741, V1742, L1743, C1744, I1745
494 Glial cell line-derived P39905 V127, F190, A205
neurotrophic factor
495 Thrombopoietin P40225 L33, L56, V60, L62, A81, I84, L85, V88, L91, V95, A98, L111, L114, V118, I148, F149, F152, L156
496 Thrombopoietin receptor P40238 L30, L31, C40, F41, F45, L48, C50, F51, W52, L65, Y67, C77, C93, F95, V101, L103, F104, L107, L109, V111, V127,
V130, L132, A134, I139, A141, L150, I152, W154, F164, L165, Y167, L234, L246, Y252, W269, W272, L396, I401,
L406, L408, W410, A418, Y423, Y427, W435, V437, L438, A444, L449, L451, Y457, A463, Y470, W474, W477
497 B-cell antigen receptor P40259 V61, M63, C65, W76, A105, L107, I109, Y120, C122
complex-associated protein
beta chain
498 Alcohol dehydrogenase class P40394 A24, A25, V26, L27, F34, I39, V41, V49, I51, I53, A55, I58, H64, V65, V76, I77, V78, H80, A82, V96, V102, I103, L105,
4 mu/sigma chain (EC L107, C116, C124, L135, A136, F142, C144, V149, H151, F152, F158, V163, V164, V169, A170, I172, A176, V181,
1.1.1.1) C182, L183, I184, F188, Y192, A194, A195, C207, V208, V209, F210, L212, L217, V219, I220, C223, I231, I232, I234,
A244, I253, V265, L266, V274, F278, A290, L291, C294, V302, V303, F331, V340, L343, V344, L354, L357, F364, I367,
F371, V383, L384
499 Leptin P41159 I35, I38, L72, M75, L79, Y82, I85, I97, L101, L104, L108, A112, A146, L150, L154, M157
500 Extracellular calcium- P41180 A46, V115, I135, F320, A321
sensing receptor
501 Aquaporin-2 P41181 I112, L116, A127, C181, M183, A186, A190, A192
502 Glycine--tRNA ligase (EC P41250 M124, L128, F133, A137, L157, I161, W165, F169, L189, V203, A214, L218, L222, M239, L254, L280, A301, I304, F305,
3.6.1.17) F308, A323, A324, A349, I351, F354, V368, A369, L373, A380, A387, L392, A395, I401, V405, L406, F409, I410, I413,
Y416, L417, V420, L427, F429, W445, A447, I458, V459, C461, C466, L469, L480, A482, A503, I504, V515, I521,
I542, L551, V574, I575, F579, L581, I584, M585, Y586, V588, F589, F593, F605, F607, V611, A612, C616, V618, L619,
F627, L634, L638, V643, Y658, V666, A667, F668, V670, I672, A684, L686, I695, A697, L702, I705, V706, V719
503 T-lymphocyte activation P42081 A36, L38, C40, L53, V54, V55, L95, L97, L100, C110, I111, I112
antigen CD86
504 Glutamate receptor 1 P42261 I25, I27, L30, F31, A41, F42, L46, L55, M70, F74, V82, A84, I85, F86, V94, L97, C101, V106, F108, I109, F113, F121,
V122, L123, L125, L129, A132, L133, I136, I137, F145, V146, Y147, V161, A165, I177, L192, V200, V201, V202, C204,
L209, L213, I216, I217, Y228, I229, L230, A231, L233, F235, F243, A248, V250, F253, V256, I266, W270, V281, A291,
L292, V297, V299, M300, A303, F304, L307, A320, I337, A340, L341, L349, V353, L366, V368, Y409, I410, V411,
Y419, V420, L422, F429, Y435, Y438, C439, V440, L442, A443, A444, I446, A447, L456, A466, M477, V478, L481,
A486, V488, A489, V490, A491, L493, I495, I503, F509, L512, I514, I516, M517, I518, I647, L653, A654, Y661, F672,
F673, M684, Y687, M688, V695, V697, M704, V707, Y714, A715, Y716, L717, L718, Y725, Y746, I748, A749, V760,
A763, V764, L765, L767, L772, L773, L776, W780, W781
505 Glutamate receptor 3 P42263 I34, I36, L39, F40, A50, F51, V55, F69, L71, V86, F90, V98, A100, I101, F102, M110, L113, C117, F124, V125, F129,
F137, V138, I139, M141, L145, A148, I149, L152, L153, F161, V162, Y163, I177, A181, V193, M209, Y217, L218, I219,
C221, I226, L230, V233, V234, Y245, M246, L247, A248, L250, F252, V260, A265, I267, F270, V273, V280, F283,
W287, A298, A301, L303, A308, L309, A313, I314, V316, I317, A320, F321, L324, A337, I354, A357, L358, M366, I370,
I383, V385, I425, V426, V427, Y435, V436, Y438, L445, Y451, Y454, C455, V456, L458, A459, Y460, I462, A463, L472,
A482, M493, V494, L497, A502, I504, A505, V506, A507, L509, I511, I519, F525, L528, I530, I532, M533, I534, I665,
L671, Y679, F690, F691, M702, Y705, M706, V713, V722, V725, F732, A733, F734, L735, L736, Y743, Y764, V766,
A767, V778, A781, V782, L783, L785, L790, L791, L794, W798, W799
506 Phosphatidylinositol 4,5- P42336 M16, L21, V22, C24, L25, L26, M30, I31, V32, C36, L42, I45, L49, A53, L61, I69, F70, V71, V73, F82, F83, L89, L92, L94,
bisphosphate 3-kinase F95, L99, V101, I117, A120, I121, V125, F128, V136, F139, I143, L144, C147, A150, A163, Y165, I181, I190, V192,
catalytic subunit alpha V193, I194, L209, I211, V220, I221, A222, A224, L239, L244, L252, V254, C255, C257, Y260, F261, L262, L267, Y270,
isoform Y272, I273, C276, L285, L293, L327, I330, L334, I336, I338, A341, I354, Y355, V356, I360, Y361, V376, L387, Y389,
I393, L396, A399, A400, L402, C403, L404, I406, C407, V409, C420, L422, A423, L429, F430, L443, L445, L452, L456,
V461, L473, L475, V484, I492, A496, L531, I534, L540, L551, C558, V559, I564, L565, L568, L569, L570, V580,
A581, M583, V587, I593, A598, M599, L601, L602, V611, F614, A615, V616, C618, L619, L628, Y631, L632, L635,
V636, V638, L639, L648, L649, V650, L653, L654, A657, L658, I663, H665, F667, F668, W669, L671, V680, F684, L686,
L687, L688, Y691, C692, A694, C695, Y698, L699, L702, V706, A708, M709, L712, L715, I718, L719, L735, M739,
F744, A747, L748, F751, L755, L761, L764, C769, I771, L779, L781, W783, I788, M789, L792, L793, I799, F801, L807,
L812, L814, I816, I817, M820, W824, L831, M833, L834, L839, L847, I857, I860, L877, H878, L881, A893, L896, F897,
C901, A902, Y904, C905, V906, A907, F909, I910, L911, I913, I921, M922, V923, L929, F930, H931, F934, F937, L938,
F954, F960, L961, I962, V963, I964, C971, F977, F980, C984, A987, Y988, A990, I991, A995, F998, I999, L1001,
F1002, M1004, M1005, M1010, L1013, F1016, I1019, Y1021, I1022, L1026, A1035, F1039, M1043, W1051
507 Protein AF-9 P42568 V7, L11, L13, H15, A17, V34, V36, F47, V48, V51, V52, F53, Y71, I82, L83, I85, V87, F89, Y102, L104, F131, L135,
I522, I526, I530, V555, L558
508 Dipeptidyl aminopeptidase- P42658 V131, V133, F156, V165, A201, L202, V220, L242, A245, I255, F256, I257, I262, W291, L292, Y293, A303, A314, I318,
like protein 6 L328, L356, H357, V358, L361, L368, M370, Y382, I383, V394, A395, V396, W398, I407, C411, A413, W429, F447,
H462, I463, V487, I500, F502, L514, A517, V520, L528, C536, F550, C554, V564, H565, L606, M608, I610, L624,
L625, M649, V650, A655, V656, V657, L672, V676, M689, V692, M695, V706, A707, V708, Y716, L717, I721, F733,
C735, A738, I742, F745, A749, A751, L757, Y767, V772, V776, L785, I786, I787, H788, I795, F797, H799, L807,
I839, F843
509 Leukemia inhibitory factor P42702 V81, I112, L134, L153, V170, V176, L211, H216, V218, I220, V254, F269, C270, C271, V277, A280, I299, V314, F316,
receptor I327, A329, I349, C351, W353, L371, F397, Y406, F408, L410, A412, I427, V431, L451, F459, C466, I468, V494, I509
510 Wiskott-Aldrich syndrome P42768 F258, L267, L270, F271, L281, I290, F293, I294, V303, L326, I438, L470
protein
511 Growth/differentiation factor P43026 C400, F409, C433, A447, I476, C498, C500
5
512 Platelet-activating factor P43034 V111, M123, V124, A126, I132, L146, V153, L165, A166, C168, I174, L176, W177, M188, V195, V198, I207, V208,
acetylhydrolase IB subunit A210, I216, W219, V237, V240, I249, A250, C252, V258, V260, L272, V279, C281, L311, L312, I320, L334, V341,
alpha I353, L354, C356, A357, L362, W365, Y367, V383, V396, V404, V406
513 Cathepsin K (EC 3.4.22.38) P43235 I44, L48, Y126, V130, C136, C139, W140, A141, A147, L148, L159, L162, L167, V168, V171, A185, F186, V189, I195,
Y201, M211, A219, C221, I227, L235, A238, V239, V242, V245, V247, A248, I249, A251, F256, F258, Y264, Y265,
L274, H276, A277, V278, L279, A280, V281, Y283, W292, I294, W302, I308, M310, A311, A317, C318, I320, A321,
L323, A324
514 Hemagglutinin [Cleaved P43258 A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, F94,
into: Hemagglutinin HA1 C97, Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180,
chain; Hemagglutinin HA2 V182, H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,
chain]/strain A/Duck/Hong C281, I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
Kong/64/1976 H3 I478, I481, A495
515 Hemagglutinin [Cleaved P43259 A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, Y94,
into: Hemagglutinin HA1 C97, Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180,
chain; Hemagglutinin HA2 I182, H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,
chain]/strain A/Duck/Hong C281, I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
Kong/231/1977 H3 I478, I481, A495
516 Hemagglutinin [Cleaved P43260 A11, L13, C14, L15, A19, V26, V36, L42, V43, I51, C52, I58, C64, L66, I67, L70, L71, C76, F79, L86, F87, V88, F94,
into: Hemagglutinin HA1 C97, Y98, Y100, Y105, A106, L108, V112, A113, L118, F125, A138, C139, F147, F148, L151, L154, L164, Y178, W180,
chain; Hemagglutinin HA2 V182, H183, H184, Y195, V202, V204, I230, I232, Y233, I236, V237, V242, L243, I245, L251, I252, A253, F258, I274,
chain]/strain A/Goose/Hong C281, I282, I288, V309, L316, A317, A334, W343, Y351, A373, A425, L447, L455, C466, F467, I469, H471, C473, C477,
Kong/10/1976 H3 I478, I481, A495
517 Neuronal acetylcholine P43681 A141, H142, A155, V165, I189, L191
receptor subunit alpha-4
518 2-C-methyl-D-erythritol 2,4- P44815 H11, L19, I20, I21, V26, F32, I33, A34, V40, A41, L42, H43, A44, L45, A48, I49, L50, A52, A53, I58, L77, L78, A81, V85,
cyclodiphosphate synthase/ I92, V95, I97, I99, M106, I110, M113, A115, I117, A118, L121, I125, V128, A132, I147, A148, C149, A151, A153, L154,
strain ATCC 51907/DSM L155, I156
11121/KW20/Rd
519 Aspartoacylase (EC P45381 I11, V14, A15, I16, F17, V31, I41, A57, L69, F73, A93, I96, F100, I111, I112, F113, M122, C124, L126, L128, L136, I137,
3.5.1.15) M139, F140, I143, V154, L156, I170, V175, I177, V179, M195, M198, A202, L203, F205, I206, F209, I220, V222, I225,
A241, L247, V281, V283, A294, F295, A296, I308
520 Short/branched chain P45954 A72, I76, M83, V93, L97, M103, I105, V107, V122, L123, V124, I125, L128, A129, A133, V135, A136, C139, I146, L149,
specific acyl-CoA I150, L163, L166, C175, A181, A192, L201, I208, A211, A214, L216, F217, L218, V219, M220, A221, I232, F235,
dehydrogenase, L236, V237, L244, C261, L263, V268, V270, L276, A286, I295, I297, A298, A299, M301, L302, L304, A305, C308, I316,
mitochondrial L332, L343, A346, A353, A354, A367, A370, A374, A378, C385, V400, A407
521 Chemokine XC receptor 1 P46094 A26, W27, V28, F29, A30, L32, A33, V36, L37, C39, L40, F42, L46, V47
522 Large proline-rich protein P46379 V19, V21, A35, V39, F42, I46, V50, L59, L72, V77, I82, L84
BAG6
523 Vesicle-fusing ATPase (EC P46459 V23, I74, F121, V514, A551, A554, L623, L627, L677
3.6.4.6)
524 Neurogenic locus notch P46531 C423, C438, C449, C456, C461, C487, C525, C942, C1056, C1180, C1454, C1467, C1496, C1509, L1515, C1536, L1574,
homolog protein 1 V1575, V1576, V1577, V1578, L1585, F1592, L1596, L1600, I1616, V1676, L1678, I1680, C1685, A1696, V1699,
A1700, L1703, A1705
525 40S ribosomal protein S10 P46783 L15, F16, M21, A23, V45, A48, M49, L79
526 E3 ubiquitin-protein ligase P46934 G451, Y463, L499, L529, L563, Y785, F858, F948, M964, I979, L988, A990, L992, F996, A1008, W1011, F1012, I1015,
NEDD4 (EC 6.3.2.—) M1019, F1027, F1054, F1056, I1057, V1060, A1061, M1063, A1064, V1065, L1071, F1075, Y1080, M1083, L1084,
M1093, L1104, F1119, I1121, V1143, Y1151, V1155, M1168, F1171, F1175, L1178, I1179, I1184, F1187, L1192,
M1196, C1197, W1207, V1223, I1224, F1227, W1228, A1230, V1231, L1242, L1243, V1246, F1257, L1260, F1269,
V1271, L1290, L1292, L1301, L1305, I1309
527 3-hydroxyanthranilate 3,4- P46952 L32, I48, L64, V66, L85, V89, V100, V104, L116, Y119, L194, V211, A213, L230, L248, L255, A272
dioxygenase (EC 1.13.11.6)
528 F-actin-capping protein P47756 A9, L25, L39, L60, V119, Y120, A129, V131, L133, I134, H152, V154, V156, A165, Y167, L169, V173, M174, V217,
subunit beta M220, I224
529 Tumor necrosis factor ligand P48023 A147, L149, L160, L181, I183, Y189, V191, V195, F197, L207, H209, V211, L257, V259, F276, L278
superfamily member 6
530 Stromal cell-derived factor 1 P48061 I59, A61, I72, I79
531 Glycine receptor subunit P48167 V80, V82, V84, I86, Y101, V103, I105, W111, L116, L128, L163, I165, V171, I179, L181, C183, L187, F190, C197,
beta M199, L201, L211, F213, C255, V256, V258, F260, L262, V273, I280, V281, F288, L309, A328, L329, L333, C336,
V350, M353, A370, A470
532 Transcription factor SOX-9 P48436 V114, A116, L123, L135, L139, F154
533 G protein-activated inward P48544 W108, A139, L168, A206, V207, I208, L217, V221, I234, A236, L238, L252, I257, L274, M289, V301, V303, L305,
rectifier potassium channel 4 A318, Y322, F351, A368
534 T-complex protein 1 subunit P48643 A33, A41, M48, A75, I77, I87, M91, V109, V110, A113, L116, L123, I133, A140, A144, A169, L173, A186, A189, A192,
epsilon V204, I229, M239, A246, I248, A249, I250, L251, F255, I289, I292, A297, L299, A300, I301, C302, A310, L314, L319,
A321, I330, I333, A356, V359, V373, I374, I385, F386, I387, L402, A405, V408, I409, L412, V419, A424, A425, I427,
A430, V433, A437, F451, A452, A454, A461, V477, L510, A520, I527
535 Protein ERGIC-53 P49257 V64, I80, V82, A83, V93, W94, A99, V106, V108, F110, V112, A120, L123, A124, W126, Y127, A128, V137, F138, V147,
F150, F151, I165, I167, I168, I174, F194, V201, A203, I205, L212, V214, I216, A231, F244, I246, A248, H257,
V259, F262, F265
536 Alpha-aminoadipic P49419 L33, L42, Y55, C70, I77, A78, V80, V92, A95, A98, W102, V114, I117, L121, I125, L128, L131, V132, L134, M136,
semialdehyde V147, Y150, V151, I153, C154, A157, I179, L187, V188, I190, I191, V198, A199, V200, Y201, A206, I207, A208, M209,
dehydrogenase I210, C211, V214, C215, L216, W217, L225, I226, V228, A229, V230, I234, L238, A246, I247, L250, C252, I257, A260,
M261, A262, V267, L269, L270, V286, L294, A302, I303, I304, A305, V314, A318, A321, A326, A333, L336, F337,
I338, V346, L350, Y369, L372, F381, A384, V385, A388, Y408, V409, I413, V414, A424, A430, I432, L433, V435, F436,
F438, V444, L455, I459, F460, W470, Y516
537 Alanine--tRNA ligase, P49588 I10, F14, F17, F18, A42, A44, M46, F49, A69, A70, C75, I76, F97, L101, W104, C115, M117, A118, L121, L122, Y134,
cytoplasmic (EC 6.1.1.7) V135, F138, C152, W156, C184, C187, I190, H191, A200, L212, W215, L217, F219, I220, I238, M242, L244, L247,
V248, Y258, F263, Y266, I270, A288, A294, Y295, V297, L298, A299, H301, A302, I305, V307, A308, L309, L324,
I327, L328, A331, V332, A335, L339, F346, A347, L349, V350, V353, L357, F361, I375
538 Prolactin-releasing peptide P49683 A44
receptor
539 Cartilage oligomeric matrix P49747 C287, C292, C328, C351, C387, C410, C448, C484, C504, F531, L539, L570, A571, V572, F577, F582, H587, V588,
protein Y596, A597, I600, F601, F609, Y610, V611, M613, A629, A631, I635, L637, A639, V640, L650, A653, L654, W655,
V664, W684, L686, H688, Y694, I695, V697, M717, L722, V724, F725, C726, I732, W734, A735, L737, C741
540 Presenilin-1 P49768 V89, C92, M93, V96, A136, I213, L226, A231, A234, L235, A246, V261, A285, V379, L381, F386, Y389, V391, L392,
V393, A396, C410, I414, I439, M457
541 Bis(5′-adenosyl)- P49789 F23, A24, V36, L37, V38, C39, L58, V65, V69, H94, V99, A139, L142
triphosphatase (EC 3.6.1.29)
542 Presenilin-2 P49810 V95, C98, M99, V102, I219, L232, A237, A240, L241, A252, V267, A291, L362, F367, Y370, L373, V374, A377, C391,
I395, I420
543 Glycine amidinotransferase, P50440 V66, W72, V78, I79, V80, A83, A86, C87, V88, V95, A97, Y107, F115, A123, I127, M130, C131, L134, L163, Y164,
mitochondrial (EC 2.1.4.1) A166, M167, I171, L172, I173, V174, I179, I180, A182, M184, A185, W186, A195, Y196, I200, Y203, M218, L222, I229,
V245, C252, F253, A255, A256, I259, A261, I265, F266, A267, V272, M281, I294, I304, F308, I310, I311, V316, L317,
F330, M353, M360, V362, L363, M364, L365, V370, M371, V372, I379, F383, V393, I395, A398, L401, F405, H406,
W408, C410, V412
544 Serpin H1 P50454 L102, V107, A109, A203, V226, M271, L324
545 Dynamin-2 (EC 3.6.5.5) P50570 V13, L16, F20, L29, I34, A35, V36, V37, A42, V47, L48, F51, V52, F56, L57, L69, L71, L73, I74, A81, F83, F91, V97, I120,
L122, V124, V129, L132, L134, I135, L137, I140, I152, I156, I160, I164, I171, L172, A173, V174, A177, A186, A190,
V193, I201, V203, I204, L207, A216, I232, V234, F259, Y265, A269, L277, L281, L285, I289, L293, L300, L304, L305,
F336, F340, F370, L374, L384, I388, I392, A408, F409, V413, V417, C424, C427, V428, V431, L435, V439, C442, L452,
I459, V460, I475, I479, L526, I528, Y541, F543, L545, L550, W552, I572, F586, A587, I588, F589, I603, L605, C607,
V613, W616, F620, V625, V664, M675, I679, M683, I691, L695, L699, L729, A732
546 Palmitoyl-protein P50897 V36, V88, V95, L99, L105, F120, A123, V124, H143, F147, C160, I163, V181, A183, Y195, F201, L202, A203, I205,
thioesterase 1 Y215, L222, V228, F230, L258, L263, L269, L283
547 Sodium/potassium- P50993 H42, L44, L49, A66, L102, A106, C109, V133, V138, V169, I170, V183, V184, L188, V189, A199, L201, I203, C209,
transporting ATPase subunit V211, C241, F242, C247, A252, I255, V256, A272, I286, A297, A318, I320, F321, I325, L334, V340, A346, C354, V362,
alpha-2 C372, L379, M384, A387, M389, W416, A418, L419, I422, A423, L425, C426, A429, V440, A453, L454, V465, L488,
I490, H491, H500, V501, L502, V503, M504, I511, L519, Y539, L542, F552, C553, L557, L580, C581, F582, V583,
L585, M588, A594, V596, A599, V600, C603, A606, I608, I611, M612, A621, A623, A625, I630, I631, A642, A643, A657,
A659, I685, V686, F687, A688, I698, V699, C702, V709, V716, A721, L722, A725, I727, I729, A730, M731, I746,
L747, F752, V759, L764, I765, Y775, L777, F790, L799, I807, A816, L819, L841, V842, L846, A850, I854, Y866, I869,
L870, F875, L880, W887, C915, A918, F919, F920, A921, I923, V924, V925, V926, L931, I933, C934, L951, L955, A962,
L975, M977, A988, I995, L1006, Y1020
548 Ras-related protein Rab-7a P51149 L9, V11, I12, I13, L14, V19, L24, M25, Y28, V52, V57, M59, I61, A65, Y78, C83, C84, V85, L86, V87, F88, V90, L99,
F106, F120, V121, V122, L123, V134, A139, C143, A156, V162, A165, F166, I169, A170, A173
549 Ras-related protein Rab-27A P51159 L13, Y27, L96
550 Transcription activator P51532 M1462, I1465, V1466, V1469, I1501, F1507, I1510, I1514, L1525, V1529, C1533, A1536, L1553, F1557, V1560
BRG1 (EC 3.6.4.—)
551 Galactokinase (EC 2.7.1.6) P51570 A16, V32, A34, L53, V64, V73, A107, V110, V113, A120, A127, V128, V130, V133, L139, A143, V147, A148, F152,
L153, A167, C170, A173, V211, I222, C243, V246, L255, L263, A266, A278, H280, V281, A291, A292, A294, Y318,
C322, L328, V329, A332, C351, L356
552 Methyl-CpG-binding protein P51608 L124, F132, L138, F142
2
553 Fatty aldehyde P51648 V8, L27, A29, L30, M33, V34, I41, I45, L49, V56, V61, V64, I68, M71, L75, V104, V105, L106, I107, F115, L117, I119,
dehydrogenase (EC 1.2.1.3) L122, I123, A125, I126, A127, A128, A131, V132, I133, I134, L150, L151, L159, Y160, L173, F182, V193, A196, A197,
C214, I216, V225, C226, I229, Y234, C237, I247, L248, C249, I257, I261, I282, F288, I291, L294, I313, A314, V317,
L318, V327, M328, I332, I336, L337, I339, A348, L359, A360, L361, Y362, V363, F364, M374, V388, Y410, F419
554 C-C chemokine receptor P51681 Y187
type 5
555 N-sulphoglucosamine P51688 A25, L26, L27, L28, L29, A30, L58, F60, A63, F64, V67, A75, L77, L81, M88, L107, L111, I120, I121, V126, V131, Y132,
sulphohydrolase (EC I152, I155, V159, F162, F171, F172, L173, Y174, V175, A176, F177, F193, C194, I207, A232, L236, Y240, V250,
3.10.1.1) V253, L257, L267, I276, F278, L285, V296, A311, V313, L318, I322, L323, L348, A351, M376, V379, L386, F408, L411,
L438, L464
556 Arylsulfatase E P51690 M61, L163, L292
557 Amyloid-like protein 1 P51693 F395, A398, V409, L413, L467, L477
558 Potassium voltage-gated P51787 W379, W392, I394, I396
channel subfamily KQT
member 1
559 Chloride channel protein P51800 V547, L558, A559, V567, Y579, V582, V594, L599, L618, L635, L641, A644, F648, V658, V668, M673, A676
ClC-Ka
560 Ribosomal protein S6 kinase P51812 V85, A93, A98, I121, F129, V131, I146, L155, F165, V170, Y173, L174, A175, L177, A178, A180, L181, L184, L187,
alpha-3 I189, I190, Y191, L194, I199, L201, H206, I207, L209, F212, A225, A236, H245, A249, W251, W252, F254, V256,
L257, M258, M261, F268, I280, L281, L285, F290, A295, L298, L299, L302, A308, V318, I321, F327, L335, A347, C439,
V450, I453, I464, I466, L467, Y470, I476, V491, V492, L501, L502, I505, L506, A516, L520, I523, V527, L530, V535,
V536, H537, L540, I545, I557, I559, F562, M576, I601, L604, V606, L607, L608, Y609, M611, L612, F618, A619, I629,
W645, A652, L655, V656, M659, L660, A670, V673, W678, V699, A702
561 Cytoplasmic tyrosine-protein P51813 V442, V444, A461, L467, L472, V478, C479, V488, L497, L513, M516, C517, V520, C521, M524, L527, L537, A538,
kinase BMX (EC 2.7.10.2) A539, C542, V544, V550, V552, V561, A580, V595, W596, F598, I600, L601, M602, V605, F606, V621, A637, M645,
C648, F659, I666
562 Spermine synthase P52788 L9, F11, L13, L26, F30, A36, L48, A49, Y51, A59, L61, I63, V69, L71, L73, I89, V93, Y134, I150, I152, I161, I163, I181,
V194, L195, I196, L197, I204, L205, I208, V216, M218, V219, C229, V259, L260, Y263, V273, I274, I298, L299,
M303, V305, L306, F313, V348, Y358, V360
563 Ephrin-A5 P52803 V34, W36, I50, V52, L58, V60, Y77, L79, C102, F118, F130, Y138, I139, L154, V156, V158
564 Biliverdin reductase A P53004 V11, V12, V13, V14, V16, F42, A62, V70, A71, Y72, I73, H80, I84, F87, L88, V94, L95, V96, M100, A107, L110, H122,
L136, L150, A166, F167, I170, L173, W175, L176, M201, V203, L205, L213, W215, F231, F258, I278, C281, L282,
A285, I288
565 Collagen alpha-4 P53420 L1468, L1494, Y1495, L1507, Y1541, W1542, L1543, V1563, C1566, A1567, V1568, C1569, A1571, F1601, H1604,
C1622, F1631, L1632, C1634, C1641, C1683, V1685, C1686, V1687
566 Dipeptidyl peptidase 1 (EC P53634 C30, L35, W39, F41, V66, L68, A74, F84, I86, I87, F92, I94, F102, A103, F105, H127, W134, C136, F137, Y259, A262,
3.4.14.1) M264, M266, A269, I271, L283, V288, Y294, Y304, L305, I306, A307, A311, L316, V317, Y347, Y352, M360, L364,
M370, A371, V372, F374, F380, V407, L408, L409, V410, W423, V425, F439, I441, I450, A454, A456, A457
567 DNA polymerase subunit P54098 F139, A143, A153, L157, W175, Y178, A194, L195, V196, F197, C202, A212, V213, A214, I215, A219, W220, C224,
gamma-1 (EC 2.7.7.7) A242, L244, A253, L265, V266, V267, A276, I278, Y282, M289, M297, H298, A300, I301, L304, V359, M393, A397,
V400, V406, F407, V422, A425, M427, L428, V432, Y434, L435, V437, W441, A448, L463, A467, F610, I798, W801,
A804, I808, A839, L841, A847, V870, L874, A876, V878, A880, V887, A889, V891, I898, A899, A900, L902, A908,
A915, A936, A982, A1045, L1061, C1077, I1079, A1082, W1099, V1100, V1101, A1105, V1106, Y1108, H1110, L1111,
L1113, V1114, A1115, M1116, L1119, C1130, Y1139, L1140, V1141, A1149, A1150, A1152, L1153, C1162, M1163,
A1165, L1168, A1178, A1182, V1183, C1197, A1217, L1218
568 Tyrosine--tRNA ligase, P54577 I14, L27, L36, I38, Y39, F53, M56, I59, F62, C67, V69, I71, F73, H77, A78, A85, V94, Y96, Y97, V100, I101, M104, L105,
cytoplasmic (EC 6.1.1.1) Y129, L136, A171, L172, A181, F183, I191, F192, A195, L199, V208, H209, L210, M211, I232, L234, V241, L245,
V260, L261, I264, V267, I277, Y289, L295, F299, V304, L309, V313, L317, L321, I324, L336, A339, A340, I370, V372,
I375, I392, V394, V402, V403, L406, L415, V420, V421, V422, L423, L440, L441, C442, A443, L455, V469, L491,
F495, I497, A503, F510, I517, C519, I527
569 Ephrin type-A receptor 4 P54764 I67, V72, L84, I89, A94, V97, Y98, I99, I101, F103, L105, V114, F122, L124, I148, V157, V173, F181, Y182, L183,
(EC 2.7.10.1) A184, F185, A190, I192, A193, L194, V195, V197, V199, C204, A212, F214, M245, C247, C273, C276, C325, V344, L346,
V398, I400, Y409, F411, I413, A415, V419, V434, A440, V447, V457, L459, V476, I500, Y509, F511, V513, A515, A519
570 Alpha-N- P54802 V32, L35, V36, L67, V75, V77, V83, A84, A85, A86, L89, Y92, C99, Y132, I154, M157, A158, I162, L164, A165, A167,
acetylglucosaminidase (EC I174, V178, A181, I189, A197, F198, A200, L230, M233, F236, V241, L242, F245, V253, F271, L281, I291, F295, L296,
3.2.1.50) Y309, L327, V334, M338, A345, F354, A368, L378, L379, V380, V390, F397, F402, I403, W404, C405, M406, L407,
L420, A430, A444, V453, V454, L457, V475, F478, A479, A490, A493, V501, L517, V518, V536, F537, A539, W540,
L550, F556, L560, L561, L563, A567, V568, L571, V572, Y575, L584, L591, V597, L598, A599, L602, L603, L606, V609,
L610, F616, L618, L622, A625, A635, Y638, L646, L648, W649, A659, L666, V667, Y670, Y671, W675, F678, L679,
L682, V701, V709, V724, A727, Y734
571 Galactocerebrosidase P54803 L83, L95, L98, F437, V576, V607
572 Adenylate kinase 2, P54819 I16, A18, V19, L20, L21, A26, A32, L35, F39, V41, L64, V80, L82, I83, F96, L97, L98, F101, A108, L111, M115, L122,
mitochondrial V125, I126, F128, L134, L135, I139, L143, H145, A182, L183, L187, L197, Y200, Y201, I210, A212, I223, F227
573 Allograft inflammatory P55008 L24, L47, F50, Y54, F57, L59, I65, L70, M73, L74, L86, I90, F101, Y103, F106, L107, A116, L118
factor 1
574 Transitional endoplasmic P55072 L26, V28, V38, V39, L41, M46, V57, L59, A67, V68, C69, V71, I82, M84, V88, L92, V94, I100, I102, C105, I114, V116,
reticulum ATPase I119, Y134, L135, F139, L153, V154, V161, F163, V165, V166, C174, V176, A177, V181, C184, A214, I216, V220, I241,
L242, L243, Y244, I254, A255, A257, V258, A259, I269, I274, L286, A289, F290, A293, A299, I300, I301, F302,
I303, L306, I309, A310, I324, V325, L328, L329, M332, L335, V341, I342, V343, M344, A345, A346, I353, L357, F363,
V367, I369, L381, V399, A400, H406, V407, L411, L414, C415, A418, A419, A422, A439, V447, F452, A455, L489,
V493, V514, L515, F516, L527, A528, A530, I531, A532, F539, I540, I542, L547, L548, V559, F563, A566, C572, V573,
L574, F575, F576, I582, V600, I601, M608, I619, I620, A622, L639, I645, L657, A676, L687, I690, A694, I731, H735,
A739, V747, I752, L762
575 Fibroblast growth factor 8 P55075 L74, V83, V85, A93, A95, A102, I126, C127, M128, I135, C145, F147, A158, M169, A170, F171, V190, F192
576 Laminin subunit beta-2 P55268 C519
577 Cadherin-8 P55286 V70, F109, I118, A120, L124, L134, A138, I154, I155, V157, V176, V189, A223, I224, I225, V242, I244, A246, L262,
V264, A300, F324, L353, V355, A357, V378, I380
578 Cadherin-15 P55291 L138
579 FAD-linked sulfhydryl P55789 A114, A115, A146, L153, F166, L170, C171
oxidase ALR (EC 1.8.3.2)
580 Eukaryotic translation P56537 F7, I13, A17, Y23, C24, L25, V26, A27, F34, F38, V49, I53, I59, V64, L70, L71, V72, I84, V97, L104, V107, A115, L116,
initiation factor 6 V117, L129, L133, V142, V148, V153, L160, V161, L173, L177, V179, V186, I193, A194, M197, V198, C203, A204,
F205, C206, V218, F222
581 Ubiquitin-associated and P57075 L28, A38, A41, L42, A53, L57
SH3 domain-containing
protein A
582 Ras-related protein Rab-25 P57735 V15, V16, L17, I18, V23, L28, L29, V47, A60, V61, A63, I65, A69, Y74, A76, Y81, Y82, A85, A88, L89, L90, V91, F92,
L94, V103, L110, V120, M121, L122, V123, V135, A140, A144, A156, L157, V162, A165, F166, V169, L170, I173
583 Anthrax toxin receptor 2 P58335 F43, L45, Y46, F47, V48, L49, V55, I62, V66, L69, A70, L80, F82, I83, V84, F85, I91, I102, L109, I120, L124, A127, I131,
I142, I143, I144, A145, L146, A159, A163, V173, Y174, C175, V176, V178, L186, I189, L206, I209, I213
584 Spike glycoprotein/SARS- P59594 V328, V337, I345, A350, L374, V382, A384, F387, V388, V389, I397, A398, I405, A406, Y410, L412, C419, V420,
CoV (Severe acute L421, A422, F483, V496, V497, V498, L499, V510
respiratory syndrome
coronavirus)
585 CD81 antigen P60033 Y127, L131, A134, V147, H151, C156, V169, L174, C190, I194
586 Phosphatidylinositol 3,4,5- P60484 L25, I33, A34, M35, A39, I50, V53, F56, L57, I67, Y68, L70, I101, F104, C105, L108, A120, A121, I122, H123, A126,
trisphosphate 3-phosphatase V133, M134, I135, C136, A137, L139, A148, A151, Y155, Y174, V175, Y180, L193, F195, M198, F200, F206, V217,
and dual-specificity protein F241, V249, V255, F257, H259, M270, F271, F273, V275, F279, V317, L325, A328, F341, V343
phosphatase PTEN (EC
3.1.3.16)
587 Interleukin-2 P60568 L34, L37, L38, L41, I44, L45, I48, M59, F62, F64, M66, L73, H75, L76, C78, L79, L83, L86, V89, L90, F98, L105, I106,
I109, I112, V113, F123, I134, V135, F137, L138, W141, F144, C145, I148
588 Proteasome subunit alpha P60900 A31, V40, A41, V42, C47, A48, V49, I50, V51, C78, V79, V91, A94, Y96, A99, L114, C115, I118, A119, C136, M138,
type-6 (EC 3.4.25.1) I139, L140, I141, V151, C154, A165, A167, A168, V195, A198, I199, C201, L202, V217, V219, V220
589 Cell division control protein P60953 I4, C6, V7, V8, V9, A13, V14, C18, L19, L20, F28, V36, F37, V42, V44, I46, Y51, L53, L55, A59, L70, Y72, V77, F78, L79,
42 homolog V80, C81, F82, V84, V85, F90, V93, W97, V98, I101, C105, F110, L111, L112, V113, I117, L129, I137, A142, L145,
A146, L149, V155, C157, A159, L165, V168, F169, A172, I173, A175, A176
590 Pterin-4-alpha- P61457 L17, W25, A33, I34, F40, A46, F49, V53, A57, V73, I75, L77, L85, L92, A93, I96, V99
carbinolamine dehydratase
591 Lysozyme C (EC 3.2.1.17) P61626 C24, L26, A27, L30, M35, L43, A44, W46, M47, C48, L49, A50, I74, F75, I77, C83, C95, C99, L102, I107, A108, A110,
V111, C113, A114, V117, V118, I124, W127, C134, V139, C146
592 Beta-2-microglobulin P61769 V29, Y30, L43, C45, V47, F50, H51, L59, L60, F82, L84, Y86, F90, Y98, A99, C100, V102, H104, W115
[Cleaved into: Beta-2-
microglobulin form pI 5.3]
593 Transforming growth factor P61812 C317, C318, L319, F326, C350, L388, I390, C413
beta-2
594 Epididymal secretory protein P61916 V37, C42, C47, Y55, V59, F61, I101, Y109, L124, W128, L130, L138, F139, C140, W141
E1
595 Ras-related protein R-Ras2 P62070 Y15, L17, V18, V19, V20, V25, L30, F34, V40, C55, I57, A62, L64, I66, L67, A70, M78, M83, F89, L90, L91, V92, F93,
V95, F101, I104, F107, I111, V114, F120, M122, I123, L124, I125, L131, V137, L145, A146, A156, A158, V164, A167,
F168, L171, V172
596 40S ribosomal protein S7 P62081 L27, L30, L36, L40, L43, I51, A59, I61, V64, F72, L79, V93, I95, L130, L133, V134, V156, F173, V176, Y177, V185
597 Actin, aortic smooth muscle P62736 A9, L10, V11, C12, C19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84, I87, W88, F92, L106, L107, A110, L112,
M121, I124, M125, F126, F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161, H163,
V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194, L195, A206, I210, V211, I214, C219, V221,
A222, I250, I252, F257, C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, L301, Y308, I311,
M315, I319, W342, I347, F354, W358, I359, I371, V372, C376
598 40S ribosomal protein S26 P62854 A78
599 60S ribosomal protein L11 P62913 L22, A36, L40, V70, V74, I82, L87, F105
600 Guanine nucleotide-binding P63092 L43, L44, L45, L46, I56, M60, I95, L99, A102, I103, I106, L113, I131, F146, A150, L153, V159, C162, C174, A175, F178,
protein G I182, I185, F219, M221, V224, A243, I244, F246, V247, V248, Y253, F273, L282, V287, I288, L289, L291, L296, L297,
V301, A337, I341, F345, A351, I372, C379, I383, H387
601 Inward rectifier potassium P63252 V161, L245, I250, I267, L298, A362, F374
channel 2
602 Casein kinase II subunit beta P67870 F21, C23, V25, I30, L36, L39, A49, I53, A75, A76, L79, Y80, I83, H84, Y87, I88, I94, M97, F106, C114, M119, L120,
V133, C137, F159, F163, L167
603 Actin, alpha cardiac muscle P68032 A9, L10, V11, C12, V19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84, I87, W88, F92, L106, L107, A110, L112,
1 M121, I124, M125, F126, F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161, H163,
V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194, L195, A206, I210, V211, I214, C219, V221,
A222, I250, I252, F257, C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, L301, Y308, I311,
M315, I319, W342, I347, F354, W358, I359, I371, V372, C376
604 Ubiquitin-conjugating P68036 A3, L7, I14, F22, W35, I39, Y46, A50, F51, I53, I55, F70, H76, I79, V104, I105, L108, L111, V112, L125, F136, A140
enzyme E2 L3 (EC 2.3.2.23)
605 Actin, alpha skeletal muscle P68133 A9, L10, V11, C12, V19, A21, A31, V32, F33, I36, V37, Y55, A60, L67, I73, M84, I87, W88, F92, L106, L107, A110, L112,
M121, I124, M125, F126, F129, V131, A133, M134, V136, A140, V141, L142, L144, I153, V154, L155, V161, H163,
V165, I167, L173, A176, M178, L180, L182, A183, L187, L191, I194, L195, A206, I210, V211, I214, C219, V221, A222,
I250, I252, F257, C259, L263, F264, I276, I284, C287, I289, I291, L295, Y296, A297, V300, M301, Y308, I311, M315,
I319, W342, I347, F354, W358, I359, I371, V372, C376
606 Hemoglobin subunit beta P68871 L4, V12, L15, V24, A28, L29, L32, L33, L49, V55, V61, L69, F72, L79, L82, F86, C94, L111, V114, L115, F119, V127,
A130, Y131, V134, V135, A139, A141, A143
607 Hemoglobin subunit alpha P69905 V11, A13, A14, W15, V18, A22, Y25, A27, A29, L30, M33, F34, V56, A64, A66, A70, V71, V74, M77, L81, A89, C105,
L106, V108, L110, L114, A124, L126, F129, L130, V136
608 Tyrosine-protein P78324 A51, L53, C55, I66, W68, I106, I111, C121, V122, F168, C170, F175, W184, A213, V215, L217, V226, C228, V230,
phosphatase non-receptor L246, I250, V271, C273, V275, F278, L285, W287, C331, V333
type substrate 1
609 Retinal-specific ATP- P78363 F1968, L1970, L1971, F1982
binding cassette transporter
610 Oxidized low-density P78380 C155, C172, L179, L180, I182, I191, I195, F202, W203, M204, L206, C243, A244, I246, V251, A260, I263
lipoprotein receptor 1
611 Protein jagged-1 P78504 F35, L37, C71, F75, L79, Y132, L134, V136, A138, I161, A177, F179, I183, V185, C196, C200, C229, C262, C265,
C293, C324, C333, C522, C560, C664
612 Reelin (EC 3.4.21.—) P78509 C674, C700, C1772, C1794, C2485, C2507
613 ETS-related transcription P78545 V72, W75, I76, C95, L102, L110, F114, L121, I279, F303, F305, V311, A312, L329, M333, L342, F354
factor Elf-3
614 C-C motif chemokine 7 P80098 C34, C35, C59, A63, V64, I65, F66, I74, A76, V83, F86
615 Protein crumbs homolog 1 P82279 C107, C221, C336, C1332
616 Mothers against P84022 V12, L15, A34, V35, L38, V39, L42, A54, I55, I65, I67, V77, Y88, C89, C109, A112, V120, C121, V122, H126, Y127,
decapentaplegic homolog 3 V130, C233, I235, Y237, V244, A250, M255, V257, L271, V283, I290, V294, L296, V303, A305, C307, I313, V315,
C320, I334, I342, F343, F348, V363, C370, I372, M374, F376, W380, C394, I396, L398, L400, L407
617 Disabled homolog 2 P98082 I124, A155, V168
618 Basement membrane- P98160 A4204, F4206, F4214, F4219, I4230, L4232, V4234, L4242, L4243, L4244, F4259, I4260, L4262, L4264, L4269,
specific heparan sulfate V4270, Y4273, L4275, A4280, V4296, A4298, I4307, V4332, I4334, C4355, V4356, L4359, L4376
proteoglycan core protein
619 Polycystin-1 P98161 A290, I294, W305, F307, H323, Y325, V333, A335, L337, V352
620 Nuclear factor NF-kappa-B Q00653 L65, V80, A89, I91, V93, V96, H105, A106, H107, I119, C120, A131, L136, M150, L174, A178, V190, L192, F194, A196,
p100 subunit I217, L228, V246, L248, L249, V260, F262, I287, V288, F289, V305, L307, L309, F323, Y325, Y326, H493, I496, I504,
I511, V520, L531, H532, A534, V543, L546, A551, A563, M564, H565, A567, L578, H605, A607, V608, L619, A637,
H639, A641, V650, L653, A675, L687, V742, L778, L782, L794, A795, L817, L818, L831, A834, L835
621 Beta-1,4 N- Q00973 I281, I299, V308, V309, I310, A311, V325, M330, L342, A343, V347, Y351, F361, V382, F426, C429, V449
acetylgalactosaminyltransferase
1 (EC 2.4.1.92)
622 Ankyrin-2 Q01484 F35, A39, V47, L65, A67, H69, L70, A71, A72, V80, L83, A100, L101, H102, A104, V112, V113, L116, L134, Y135,
A137, A138, V145, V146, L149, A168, V169, A170, A178, L182, H197, A199, A200, A208, L212, V226, L237, H238,
A240, A241, V248, A249, L252, L270, H271, V272, A273, M281, V282, L285, L303, H304, C305, A306, A307, V314,
V315, L318, L336, H337, M338, A339, A340, C347, V348, L351, V371, A372, V380, L384, L468, H469, A471, A472, V480,
L501, H502, I503, A504, V513, L516, L534, H535, I536, A538, V545, A546, L549, L567, H568, V569, A570, A571,
A579, L582, V602, A603, V611, L615, M839, V970, V974, I991, I993, V1004, C1006, V1009, A1027, I1031, V1033,
V1077, V1079, I1081, A1085, F1147, F1151, A1152, V1153, V1154, I1164, V1179, A1181, A1187, V1194, L1196,
V1220, L1222, I1233, M1235, I1237, L1260, L1261, V1289, A1297, W1300, L1301, I1302, C1304, A1314, V1317,
A1328, F1330, V1332, A1334, A1342, L1344, C1346, F1347, C1348, L1389, F1403, L1413, V1415, L1428, F1430,
L1503, L3573, I3576, A3577, L3587, A3588, I3601, L3616, L3617, W3620, A3628, L3633, L3637, I3645, M3649
623 Collagen alpha-3 Q01955 F1448, L1474, F1475, L1487, Y1521, W1522, L1523, I1545, C1548, V1550, C1551, F1583, F1586, C1604, F1613,
L1614, C1616, C1622, C1662, V1664, C1665, M1666
624 Inositol polyphosphate 5- Q01968 C28, L30, L32, A33, L41, I42, I43, I56, I58, F62, C64, C82, I84, V86, F96, I98, C104, F107, L108, V111, A114, F242,
phosphatase OCRL-1 (EC F243, V244, W247, V249, L258, W261, L262, I271, Y272, C273, I274, F276, L279, A285, W297, V301, M322, M323,
3.1.3.36) L324, L325, I326, F327, A328, V358, A359, V360, F362, F364, F369, C370, I371, V372, L376, I393, F399, I411, V417,
W419, L420, L423, Y425, V435, L447, L453, Y479, A496, W497, C498, I501, L502, L519, V527, A529, F531, I533, V535,
F572, F574, V577, I589, F599, W614, A617, L624, I632, L634, V636, V638, V643, L657, L659, L661, L669, C679, F680,
L684, L687, C688, I738, L741, V742, L745, A749, L755, L765, I768, L772, V787, A788, A790, L791, F794, L795,
V802, I803, C811, L812, V824, I825, L828, V835, F836, L839, F842, L843, L846, V855, I860, A861, F864, L868, F890,
L891
625 Tumor necrosis factor Q02223 C24, C37, C41
receptor superfamily
member 17
626 Pro-neuregulin-1, Q02297 C196, C221
membrane-bound isoform
627 Collagen alpha-1 Q02388 C2876, C2925
628 Desmoglein-1 Q02413 C58, I70, A71, I73, V83, Y85, F100, I109, I111, V115, F123, I125, C127, A129, L143, V145, V147, L179, I218, L225,
L235, V237, C255, I257, I259, I290, A305, L331, V333, L337, L347, I349, V351, I372, V374, V376, V394, A409, Y423,
L433, L442, Y460, I464, I479, I481
629 Desmocollin-2 Q02487 L185, L195, V201, F209, I211, I231, I233, I252, I304, L311, Y319, L321, I323, V325, C341, I343, V376, F404, L417,
V419, L433, I435, V437, V458, V460, A495, I506, W517, L533, Y545, I547, A551, L563, I565, I584, C585, A633, L635,
V648, I650, V652, L664, V666
630 Aminoacylase-1 Q03154 Y19, L20, A34, F38, A42, V52, V60, V62, L63, H80, V83, A98, M114, L122, M141, F158
631 Trefoil factor 2 Q03403 C31, C52, C58, C69, F70, L73, C81, C101, C118, F119
632 Mevalonate kinase Q03426 V8, A10, V14, H20, A21, V27, L29, V31, L33, L39, L41, V49, L51, L91, V109, A111, F112, L113, L115, Y116, L117, I119,
C120, L129, L143, A147, A148, V151, C152, L153, A154, A155, A156, L157, L158, I185, A189, A206, V207, A213,
L214, L233, L234, V250, I268, C275, M282, L305, V310, L315, L318, L331, C339, V353, L360, A374, V377, I379
633 Complement factor H- Q03591 Y53, I70, C87, V110, I127, C129, I249, C251, C266, A296, C317
related protein 1
634 1,4-alpha-glucan-branching Q04446 L31, L38, F45, I59, F69, C88, A92, A95, V98, L100, V136, L142, V144, V145, I146, I157, A161, V164, L197, I199, Y200,
enzyme (EC 2.4.1.18) H203, V204, I206, Y216, F219, V223, L224, I227, L230, Y232, C234, I235, L237, M238, I240, M241, H243, F249,
I253, F256, F257, A258, A259, L269, L272, V273, A276, I281, V283, L284, L285, V287, V288, H289, A292, L300, F303,
Y310, F311, H319, I334, L335, F337, L338, L339, I342, W345, L346, Y349, F351, F354, F356, V359, M362, L363, Y364,
A389, L390, Y392, L393, M394, L395, A396, L399, V400, I410, A411, M417, A419, L420, I439, W443, L446, W455,
M457, I460, L464, I474, A475, Y476, A477, H480, L490, A491, M503, I513, I517, L519, H520, M522, I523, L525, I526,
H528, L530, Y535, L536, F538, M539, F543, L549, F551, A563, L580, F583, M587, L590, W596, L597, I613, I614,
A615, F616, L621, L622, F623, I624, F625, V638, F646, L650, A654, L683, V685, I687, V691, A692, L693, I694,
L695, V698
635 Glutamate carboxypeptidase Q04609 F61, I70, L74, F77, L83, A84, A93, V108, L110, Y113, V115, L117, I128, I130, V158, F161, A163, F164, L174, V175,
2 (EC 3.4.17.21) Y176, V177, A180, L188, C196, I200, V201, I202, A203, V214, A217, V225, I226, L227, Y228, Y234, A236, V253, I258,
L259, A264, L268, A274, V287, V294, I297, A302, L305, L306, M309, A313, W319, V329, V342, M344, I346, I355, V358,
L362, V372, I373, L374, H377, V382, F383, I386, A393, V394, H396, I398, V399, F402, L405, I416, L417, F418,
A419, W421, A423, F426, L428, L429, A435, L442, V447, A448, Y449, I450, A452, I456, Y460, L462, V464, C466,
L469, M470, V474, L477, W93, W497, L515, F521, V523, F524, F525, I530, A531, A535, Y537, Y549, L551, H553,
V555, L561, V562, F565, F570, H573, V576, A577, V579, M583, V584, L587, A588, C597, Y600, A601, V603, L604,
Y607, A608, I611, V627, L632, V636, F639, A643, F646, L661, M664, L668, M669, L671, F675, L679, F686, Y687,
H689, I691, Y692, A693, F705, I708, L712, V728, I732, Y733, A735, A736, V739, A742, A743, L746
636 Copper-transporting ATPase Q04656 V10, I12, V14, M17, C22, V23, I26, I30, A48, I50, Y52, L62, I66, L173, M175, V177, I189, I193, A211, I213, Y215, V222,
1 (EC 3.6.3.54) M225, I229, F234, F281, I283, V292, I295, L299, A317, V319, L331, I335, I381, I383, M386, C391, V392, I395, I399,
V419, Y421, L431, I435, C490, I492, V503, I506, L510, I516, L520, A528, V530, Y532, I542, I546, L566, L568, V570,
I582, L586, C595, A604, I606, Y608, I618, I619, I622, A629, V837
637 Neurogenic locus notch Q04721 C315, C491, C642, C1184, C1443, C1455, C1484, L1490, C1509, C1522, W1529, L1547, I1549, V1551, L1558, F1565,
homolog protein 2 L1573, V1623, L1625, I1627, C1632, F1640, A1646, A1647, L1649, L1650, A1651
638 Activin receptor type-1 (EC Q04771 V402, L411, V424, V447, L470, L473, W478, L489, L495, I498
2.7.11.30)
639 Acetylcholine receptor Q04844 V49, I51, L53, V55, I61, V74, I76, I78, W80, V105, W106, V111, L112, A123, V128, V130, V136, W138, A142, C148,
subunit epsilon V150, W159, F166, V176, F178, V230
640 Focal adhesion kinase 1 Q05397 V39, H58, V64, I67, I68, V72, C82, L87, L124, Y128, F137, F146, F147, Y148, A160, A168, L171, C173, L174, L188,
Y194, L203, F207, A217, F228, L241, F243, F244, L247, F258, L272, A273, I274, I280, A294, I302, L316, L318, A323,
V329, A331, A337, M340, A341, L343, I344, C348, A369, I373, V436, V451, A452, I453, C459, F468, A472, M475, I483,
V489, I490, V495, I497, I498, M499, C502, L507, L511, I524, Y526, A527, L530, A533, L534, L537, I547, A548, A549,
V552, L553, V554, V560, L562, F565, L567, A579, M589, A590, V605, M607, F608, C611, M612, I615, V631, I635,
L651, L654, M655, C658, W659, F669, L672, L676, V928, L931, V932, M938, I942, Y950, V957, L961, L964, V968,
I983, L990, L997, A1004, M1020, A1024, L1027, A1028, A1031, L1034, I1038, A1041
641 External core antigen/ Q05495 Y35, F38, L44, L45, F53, A63, H81, L84, A87, A98, V118, L129, L130, F132, H133, V144, L148
genotype F2 (isolate
Brazil/w4B) (HBV-F)
642 Glutamate receptor Q05586 A71, V107, Y109, A111, Y158, I163, A236, L269, A279, A284, I301, V309, I314, I400, V401, F408, V409, C436, C454,
ionotropic, NMDA 1 C455, F458, C459, I460, L462, L463, L466, V479, M501, M502, L505, A510, M512, I513, V514, A515, L517, L538, I540,
L541, V542, L672, Y681, A682, V689, F693, M702, Y703, M706, A717, V721, L726, A728, F729, I730, W731, V735,
L736, F738, L746, F758, I760, M762, V772, I776
643 Tyrosine-protein Q06124 W6, F7, H8, A16, L19, L20, F29, L30, A31, L43, V45, I54, I56, Y63, L65, F71, A72, L74, A75, L77, V78, Y81, L88, I96,
phosphatase non-receptor L98, L102, A122, L125, L126, F135, L136, V137, F147, V148, L149, V151, I172, L190, L193, V194, V209, L210, L212,
type 11 (EC 3.1.3.48) L216, I221, A223, I226, V230, L233, F247, L254, I282, L283, F285, V290, Y304, A307, I309, I310, Y327, I328, A329,
C333, V338, F341, W342, M344, V345, V352, I353, V354, M355, C367, Y370, W371, Y380, M383, V385, L401, L403,
V419, Y422, H423, F424, W427, V439, F442, L443, V446, I453, V459, V460, V461, H462, C463, A465, I467, G468,
F473, I474, V475, I476, I478, L479, I480, I482, I483, V488, I492, V494, I498, V501, M508, V509, Y515, F517,
I518, Y519, A521, V522, I526
644 Tyrosine-protein kinase Q06187 L31, V427, I429, I432, F442, A446, M449, M450, L452, L457, V458, V463, C464, I470, I472, I473, L482, L486, L498,
BTK (EC 2.7.10.2) M501, C502, V505, C506, A508, M509, L512, H519, L522, A523, A524, C527, V529, V535, V537, F540, L542, V568,
I580, W581, F583, V585, L586, M587, W588, I590, Y591, Y598, I610, L616, A622, V626, M630, C633, W634, F644,
L647, I651
645 Acetylcholine receptor Q07001 V52, V54, L56, L58, I79, W83, V108, W109, L115, V131, V133, V139, W141, A145, C151, I153, W162, F169, I179,
subunit delta L181, I253, V330
646 Early activation antigen Q07108 Y97, A109, C113, L120, A121, I123, L132, W142, V143, L145, C173, V174, L176, I193, C194
CD69
647 Neuraminidase (EC Q07599 M83, A92, F95, I104, I112, V114, I115, F119, V120, F130, F131, L132, L156, V159, A174, A176, W177, A179, A181,
3.2.1.18)/strain C182, M189, V191, V193, A200, V201, A202, I204, V214, L222, C231, I232, C236, Y237, W238, V239, M240, A249,
A/Duck/Ukraine/1/1963 Y251, I253, A256, I261, H273, I274, C277, C279, Y280, V286, C288, V289, C290, L302, I304, L315, C316, A317, I319,
H3N8 V346, F349, F351, V357, W358, M359, I363, F371, I373, L374, I376, V393, V394, L397, F406, L418, C421, F422,
W423, V424, M426, W437, I443, V444, M445
648 Prolow-density lipoprotein Q07954 F859, C861, C879, C895, F900, C902, I908, C914, C920, C936, C943, C955, C961, F982, C984, C1002, F1020, C1022,
receptor-related protein 1 C1040, F1067, C1069, C1088, F1110, C1112, C1131, C1152, V1158, L1160, C1172, C2679, C2696, C2715, F2739,
C2741, C2759, C2781, V2786, V2788, L2793, C2794, C2800, A2804, C2812, C2818, C2837, F2863, C2865, C2884,
C2912, C2930, F3379, C3381, C3399, C3453, F3458, C3460, I3467, C3473, C3479, C3494, F3499, C3501, I3508,
C3514, C3520, C3536, C3543, V3549, C3555, C3561, C3575, F3580, C3582, I3588, C3594, C3600, C3613, C3620,
C3632, F3659, C3661, C3679, C3703, C3749, C3767
649 Hemagglutinin [Cleaved Q07FI5 V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, V74, A75, W77, I78, L79, C84, L87,
into: Hemagglutinin HA1 W93, Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A150, C152, H154, L164, L165, W166, L167, L173, L177,
chain; Hemagglutinin HA2 V189, L190, V191, L192, W193, V195, H196, H197, Y208, Y214, V215, V217, V218, I243, Y245, Y246, L249, L250, I256,
chain]/strain F258, A260, L264, I265, A266, Y269, A270, F271, A272, L273, F277, I281, I282, C291, C295, A301, I302, H312, I316,
A/China: Nanchang/11/1996 V323, L328, M330, V331, A348, M360, Y365, A387, I388, A439, L451, V458, L461, V465, L469, C480, H485, C487,
H1N1 C491, M492
650 Hepatocyte growth factor Q08048 F43, C71, A72, C75, C85, A87, F88, V89, C97, W99, L119, W153, C178, C190, F191, C207, C233, W236, C261, C272, C284
651 Interleukin-10 receptor Q08334 L38, A54, L57, C74, F76, L87, V89, A91, V108, L127, M145, V156, V189, V191, L195, V208
subunit beta
652 Epithelial discoidin domain- Q08345 M37, A72, W73, L87, V89, V97, V100, I141, M159, A161, V164, F166, L178, V180, L182, L191, Y194, A196, V208,
containing receptor 1 L210, L231, F241, Y255, V256, W258, V268, M270, F274, F280, M283, V285, C287, A295, V301, C303, F305, V336,
L338, A343, L346, C348, F350, L357, L358, F359
653 Tyrosine-protein kinase Q08881 I358, V388, I390, I393, A397, F403, A407, L418, V419, V424, C432, V434, L443, L447, L459, M462, C463, V466,
ITK/TSK (EC 2.7.10.2) C467, M470, L473, H480, L483, A484, A485, C488, V490, I496, V498, F501, V522, V541, W542, F544, V546, L547,
M548, W549, V551, V567, I571, A583, I590, M591, C594, W595, F605, L608, L612
654 ATP-binding cassette sub- Q09428 I701, I703, L708, M710, I711, V712, C717, L722, L723
family C member 8
655 Potassium voltage-gated Q09470 A347
channel subfamily A
member 1
656 Neuraminidase (EC Q0A2R1 L86, V93, A104, I105, I113, V115, Y120, V121, C123, M130, Y131, A132, L133, L157, I158, C175, V176, C183, M190,
3.2.1.18)/strain I192, C193, V194, A201, A203, V205, Y207, A219, L223, C230, V231, C232, A238, V239, V240, M241, V254, M255,
A/Chicken/Victoria/1/1985 Y256, F257, I275, C278, C280, Y281, I287, C289, V290, C291, A298, I302, I303, I305, Y316, V317, C318, V321, L322,
H7N7 V349, F352, F354, W361, L362, F374, M376, L377, I379, A382, I396, V397, F409, I410, Y420, F424, Y425, V426,
L428, V439, L446, I447, A448, L449, A465, I467
657 Hemagglutinin [Cleaved Q0A448 A26, V50, L58, C59, M60, Y65, L68, C71, V74, M76, I78, C83, W91, L94, I95, I101, C104, L115, I119, I125, M128,
into: Hemagglutinin HA1 I138, C147, Y156, L159, L162, Y178, H186, L187, I188, I189, W190, I192, H193, Y205, I212, V214, I240, F242, V247,
chain; Hemagglutinin HA2 I253, F255, H257, L261, I262, A263, V267, L270, I277, C287, C291, F292, A345, Y362, A384, L458, L466, H482, C484,
chain]/strain C488, A506
A/Duck/Germany/1949
H10N7
658 Endogenous retrovirus group Q0ED31 A54, H65, A69, M94, M99, V100, M103, L110, W111, L115, V119, V154, I165, Y193, C220, V226, I227, L228, C230,
K member 13-1 Env C241, V244, I253, L261, I272, I286, I287, V288, H289, L290, V294, I296, C298, I327, A330, C332, I334, W339, L343,
polyprotein V346, L350, I359, I360, F361, H374, C378, F382, F383, Y384, C385, L390, F391, L410, C412, I414, I417, I418, A427,
M428, I437, I443, I446, L447, L448, F462, W473, L477, Y480, V483, I485, V499, I542, L549, A552, I553, A555, L559,
L560, V564, I567, L570, V574
659 Carcinoembryonic antigen- Q0Z7S6 L36, A45, V51, L52, L53, V55, Y65, W67, I79, I80, A105, L107, M109, V112, Y120, L122, V124, F138
related cell adhesion
molecule 8
660 Spike glycoprotein/isolate Q0ZME7 F67, F103, V106, V125, I137, V138, A150, C151, C156, V162, L198, H201, F209, A211, Y212, A214, F222, Y236,
N5 (HCoV-HKU1) V237, M238, C242, Y256, Y266, L267, L268, A279, C282, L333, C352, F383, V388, F391, A392, L409, C423, Y427,
Y458, A477, I588, F589, L624, F633, A680, C719, C743, V765, I943, A1025, A1070, A1084, L1085, L1098, A1103,
A1106, F1143, I1144
661 NS3 protease Q0ZNA6 C16, V33, V35, V36, L44, A45, C47, V48, V51, C52, W53, V55, A59, L64, I71, L82, V83, W85, L94, L104, L106, V107,
V113, I114, V116, V132, L135, L143, L144, C145, A150, V151, I153, F154, A164, A166, V167, F169, V170, V172,
M175
662 Calcium-activated potassium Q12791 F815, L907, M922, C923, C943, A946, F955, L1026, A1037, I1060, A1104
channel subunit alpha-1
663 Potassium voltage-gated Q12809 I30, A32, C44, F48, C49, L51, C52, A57, V59, C64, C66, A78, I82, A83, I96, A97, F98, C105, V110, V112, L127, A763,
channel subfamily H A778, I782, I787, I804, F805, V822, A824, L830, V841
member 2
664 Glutamate receptor Q12879 M112, I116, A136, M162, F170, F177, V187, V191, V203, V217, L248, L260, V292, L307, I408, V409, F416, V417,
ionotropic, NMDA 2A V419, C436, V440, C455, C456, F459, C460, I461, I463, L464, L467, L479, W493, M496, I497, V500, A505, V506,
M507, A508, V509, L512, V522, V529, V535, M536, V537, V662, L665, F670, F682, I694, M701, M705, A716, A727,
F728, I729, A732, A733, V734, L735, Y761, I763, A764, L765, I775, A778, L779, F782, M788, L791, V807
665 Unconventional myosin-Ie Q12965 A1058, F1072, I1078, F1100
666 Glutamate receptor Q13002 L36, F38, I41, A56, F57, A60, V61, I64, L71, I83, A91, A95, L99, V103, A104, A105, I106, F107, A115, V118, C122, V127,
ionotropic, kainate 2 H129, I130, V147, L149, F153, L156, A159, I160, L163, V164, V172, V174, V175, L185, L188, A191, L197, L204,
A211, L215, M218, V226, I227, F228, A235, A236, I238, L239, A242, M247, Y254, I255, F256, L259, L261, L264,
M276, F279, L282, W296, M316, A320, A321, L322, M323, A326, V327, V329, V330, A333, M340, L345, W353, F359,
I363, A366, I375, F387, L389, V391, I392, W405, L433, I434, V435, Y443, V444, F446, L453, F459, Y462, C463, I464,
L466, L467, L470, I480, A490, M501, V502, L505, A510, L512, A513, V514, A515, L517, A518, I527, F533, L536, I538,
I540, L541, Y542, L674, A675, I680, Y682, A684, M691, F694, M705, M709, V716, V718, V728, Y733, A734, F735,
L736, M737, I742, L752, Y764, V766, I778, A781, I782, L785, L791, M794, W799
667 T-lymphoma invasion and Q13009 M40, A441, L446, V454, V467, L469, L474, F476, V497, I501, V502, V514, F515, C516, L517, A524, F527, L535, W538,
metastasis-inducing protein I542, H543, A545, C546, A547, A551, L563, M616, C623, Y624, L639, M651, F662, A664, V666, A667, A668, I848,
1 Y858, L873, A884, I895, I898, A903, L906, L920, V924
668 Secretory phospholipase A2 Q13018 F182, C204, C219
receptor
669 Platelet-activating factor Q13093 I56, C67, M71, F80, L81, Y84, Y85, W97, I98, Y103, L111, L116, M117, L124, F125, A132, Y144, L146, V147, V148,
acetylhydrolase H151, F156, I165, A168, F172, I173, A175, H179, A184, A186, Y189, V222, A226, C229, A232, L233, I239, I267,
A268, V269, I270, A277, V279, I280, L283, F289, C291, I293, A294, A297, M299, V306, I310, L314, F315, F316, I317,
I328, M331, C334, I344, F354, F357, A380, A387, L389, A390, F391, L392, F402, I422
670 S-methyl-5′-thioadenosine Q13126 I12, I14, I15, L26, L45, C55, V56, L57, L58, A76, I78, A80, L81, H88, V89, I90, V91, C95, L98, I107, V108, I109, I110,
phosphorylase (EC 2.4.2.28) A132, L152, A156, M169, V170, F186, A191, V193, V199, V202, L204, A205, I210, C211, Y212, A213, I215, A216,
M217, A218, L250, I255, I258
671 Glutamate receptor Q13224 I35, I37, A38, V39, I40, V65, I81, I85, V97, V98, F99, A100, I108, A109, I111, L112, I115, A117, I123, L124, I126, A135,
ionotropic, NMDA 2B F146, A154, V156, M157, I160, M161, F169, I171, V172, F176, F182, I186, I190, V202, L205, I216, L220, L223, I228,
L229, L230, Y231, C232, A237, I240, F241, A244, L249, W256, I257, V258, L261, V262, A263, L277, I278, V280,
V293, I299, I300, A303, A304, M307, L308, I329, L335, L339, V342, V363, I364, I365, L367, V376, I408, V409, F416,
V417, V419, C436, I440, C456, C457, F460, C461, I462, I464, L465, I468, L480, W494, M497, I498, V501, A506, Y507,
M508, A509, V510, L513, V523, I530, V536, M537, V538, V663, L666, F671, F683, I695, M702, M706, A717, A728,
F729, I730, A733, A734, V735, L736, Y762, I764, A765, I766, V776, A779, I780, L783, M789, L792, V808
672 Chitotriosidase-1 (EC Q13231 L24, V25, C26, Y27, F28, A32, A39, F41, L46, L50, C51, L54, I55, Y56, A57, F58, A59, M61, Y77, F80, L90, L93, L94, A95,
3.2.1.14) I96, F101, F106, M109, V110, F119, V120, A123, L127, F132, L135, L137, W139, F155, L158, V159, L162, F166, L178,
L179, L180, A182, A183, V184, A186, V191, V197, I200, A201, L204, F206, V207, L209, A211, H224, L228, V243,
A246, V247, W250, L260, I261, L262, M264, F271, V281, A283, A302, Y304, V306, V322, Y324, I325, W331, V332,
F334, F340, V344, L347, A355, M356, V357, A359, L360, F365, Y375, L377, I378, L381, C420
673 Noggin Q13253 L66, V173, C184, V202, L203
674 Butyrophilin subfamily 1 Q13410 A40, A46, L48, C50, A58, L63, W65, A73, V74, Y91, L109, I111, V114, Y122, C124, F126, L136, V137, L139, I208,
member A1 V364, V379, F452, F460
675 Mesothelin Q13421 I311, L315, I316, L323, C326, V327, L332
676 Alpha-1-syntrophin Q13424 L13, V31, L33, L40, V42, V88, V90, I112, I114, A122, A123, L129, A134, I135, V138, L143, A151, V162, V163, L164,
V166, M215, L236, I238, A241, L247, L249, A251, A257, I264
677 Interleukin-18 receptor 1 Q13478 I28, V31, L38, H40, W56, V82, L83, F85, V88, Y96, F98, W107, L109, F136, C140, L154, A175, C185, H187, L189,
C237, A239, L241, A278, L282, I284, C298, V300, L313
678 Myotubularin Q13496 I185, L321, Y329, I350, L385, L388, L393, F438, A455, F475, L479, I539
679 Sequestosome-1 Q13501 A8, L10, L47, V51, F55, A65, F77, A86, I97, I99, L394, M401, L413, L417, A427, I431
680 Polycystin-2 Q13563 L736, L745, L770
681 Myotubularin-related protein Q13614 A88, V91, L105, V107, L112, F114, A127, L129, V131, I132, L151, I158, L161, F163, A164, I175, L179, F184, A194,
2 W225, I227, C237, Y240, L244, V245, V246, I250, L255, V258, I267, V269, L270, A279, I281, C284, Y302, L303,
A305, I306, I316, I318, F319, A321, A327, I353, L363, L366, Y371, W388, I392, I395, L396, A399, I402, A403, V406,
V413, V414, V415, H416, A425, L427, L430, A431, M432, L433, M434, L435, Y439, I442, F445, V447, L448, V449,
W453, F456, H458, F460, H466, A472, F480, L481, F483, I484, C486, V487, M490, A497, F498, F504, L505, I508, L509,
F517, F520, L521, L533, L540, W541, I544, F551, L564, W576, Y579, Y580, I581
682 Cullin-4B Q13620 L220, A223, V224, A226, L240, A243, V244, L256, L260, C264, L286, I289, M300, I303, I306, F307, L310, V315, I324,
M327, F332, I336, I337, V342, I347, I350, L351, I354, L368, L371, L372, M374, L375, L378, Y381, F385, F389, Y397,
V410, Y413, L414, V417, L421, L428, L440, V444, L448, L449, I456, L457, L461, L464, L465, L473, L476, L479,
F480, L490, W494, I498, I505, V506, M515, V516, L519, L520, V526, I529, I532, C533, F534, F540, A543, M544, A547,
F548, F551, I552, A560, L562, I563, A564, V567, L571, L587, I590, I593, F594, I597, V602, F603, F606, Y607, L611,
A612, M629, L633, L645, M648, F708, F711, A734, L743, V745, F748, V752, I767, L778, L782, L785, A786, F808, I823,
I850, A853, I854, M858, L869, V873, L886, I890, L893, M899, Y909
683 Interleukin-10 receptor Q13651 A36, F39, H41, L43, V59, A60, L83, A98, V100, A102, F118, V123, L125, V130, Y157, F161, Y167, I169, V203, V205,
subunit alpha V209
684 Voltage-dependent L-type Q13698 A603, V610, V1010, A1023, A1312, L1329
calcium channel subunit
alpha-1S
685 Laminin subunit gamma-2 Q13753 C550, C570
686 Ectonucleotide Q13822 C59, C76, C80, F90, C94, C118, C120, C124, C130, C131, W144, L166, I167, F169, V171, F174, Y178, M186, I189, L192,
pyrophosphatase/phosphodi- M202, Y206, Y222, H226, I228, V229, M233, F242, W254, L260, A264, I280, I286, I289, L295, V303, Y304, F306,
esterase family member 2 M325, L329, V336, L339, M340, L343, C351, V352, I355, F356, V357, H360, M362, V365, C367, F372, L373, L390,
I393, I409, L412, Y424, I444, H445, L446, L447, V454, F477, M484, F488, V489, F495, V501, F504, I507, L509, Y510,
M513, C514, L517, L534, M544, A603, V604, Y610, L613, F618, Y622, M628, W631, Y634, C652, V653, V659, A669,
L681, F682, A692, A696, F697, V699, M702, V703, M705, A708, V712, W713, F716, V719, L720, V721, A725, V731,
V733, I738, F739, V757, I762, V764, Y768, Y769, I771, I772, I795, L796, V816, M820, H823, A825, V827, I830, L833,
L836, F838, I849, L850, L852
687 Plakophilin-1 Q13835 A250, L254, A266, I269, C273, A279, V283, L292, V293, V303, A306, A307, A308, A310, L311, L314, V315, L338,
I346, L350, L354, L367, A371, L372, L375, A376, V379, I380, V402, F403, A406, C409, L410, L434, M444, L450, I451,
L454, M455, V458, V472, C475, M476, V478, L479, L482, L486, L543, A548, I549, Y552, L555, A567, C568, A569,
A571, L572, L575, M582, M586, I590, L597, I600, V611, A616, L618, L619, M622, L628, M632, V636, F637, I657,
A661, V665, L668, A670, A700, A704
688 Bone morphogenetic protein Q13873 L492
receptor type-2
689 Voltage-dependent L-type Q13936 I702, V1131, A1453, M1470
calcium channel subunit
alpha-1C
690 Coactosin-like protein Q14019 C10, A12, A13, Y14, V17, W26, V27, F29, I36, F48, C52, L58, F59, A60, F61, V62, F64, A77, L78, I79, W81, I82, V101,
V104, V105, I114, L120, I125, L129
691 Heterogeneous nuclear Q14103 M99, I101, L104, L113, F117, L130, V143, V154, H160, I167, I184, V186, I198, F202, C226, I228, F230, V236, I239,
ribonucleoprotein D0 H245, V247, I254
692 Lysosome membrane protein Q14108 V42, L43, F64, F66, F67, V69, I75, Y89, F102, I109, A111, I133, L136, I138, V140, V143, I156, L160, L167, V173, L177,
2 I184, I188, L201, Y213, I228, C245, F256, F269, F273, C274, V287, A292, F293, Y295, A299, I301, L302, V323, V326,
M337, F342, F349, V350, I353, I369, I376, L377, A379, I387, V389, F395, V396, F406, V408, M409, V415, A422
693 Low-density lipoprotein Q14114 F52, C54, C72, C93, H97, I99, C111, C134, V142, C154, A158, F172, C174, L180, C192, F211, C213, A220, C234, C285,
receptor-related protein 8 C340, I350, C351, C362, C374, L424, F426, I435, L437, I446, A454, A503, Y512, L570, V601, I634, A635, I651, C700
694 Dihydropyrimidinase Q14117 L7, L8, I9, V14, V15, A23, V25, V27, V32, L35, A54, V59, L60, I64, H67, H69, M70, M75, I80, F83, A89, A90, L91,
M97, I98, I99, F101, A102, L110, I111, A113, W117, A121, V125, C126, C127, Y129, L131, H132, V133, A134, V135,
V142, M146, L149, V150, V155, F158, M160, M162, A163, Y168, V170, L175, A178, F179, C182, I185, A187, I188,
A189, V191, H192, A193, H217, A229, A233, I234, I236, A237, L244, Y245, I246, V247, H248, V249, M250, A254, A255,
I258, A261, V268, I273, A274, A275, L277, Y284, A292, A293, H295, V296, M297, L301, L311, M312, L314, L315, L320,
C328, F330, F342, I345, V349, V352, M356, V358, I359, W360, V364, F374, V375, V377, A382, A383, I385, F386, I395,
A401, I403, V404, I405, W406, I414, V423, F428, C433, V439, I441, V447, F462, I463, A469, I472, Y473, I476
695 Desmoglein-2 Q14126 L58, L64, I85, Y87, I101, F102, L111, V113, L117, F125, L127, A131, L145, I147, I181, V210, I220, L227, L237, V239,
A241, A256, V258, I260, I293, V295, A308, V334, L336, V340, V352, I375, V377, F413, A415, Y428, W437, I438, I447,
Y465, V467, I469, A471, V485, I487, V515, W544, V554, L556, I568, F570, I572, L586, L588
696 Cytoplasmic dynein 1 heavy Q14204 L2837, V2838, M2953, L2956, I2993, L3115, V3352, V3472, L3645, I3669, V3780, V3790, I3811, L3856, L3947, V4031,
chain 1 L4158, L4331, F4482, L4514
697 Filamin-C Q14315 F42, C46, L50, L57, L60, L64, L70, I71, L73, L74, V100, V102, A103, L104, F106, L107, I122, I130, L131, L133, I134,
L137, I138, I143, L165, I169, V173, F181, W185, A190, L191, A193, L194, V195, A199, C203, A218, A221, M222,
A225, L229, V231, V234, I235, I240, V250, M251, Y253, L254, A278, A296, V300, A305, V312, V338, H348, V350, V352,
F354, I359, V366, A590, F592, V593, V594, C626, V628, Y630, Y638, V640, V642, A656, C665, A688, I692, A697,
C728, I740, I741, I742, V756, V758, V1065, F1083, I1085, A1090, V1119, Y1121, Y1129, I1131, I1133, I1140, A1147,
I1149, V1158, A1160, V1178, A1183, I1192, I1214, Y1216, Y1224, I1226, I1228, Y1230, V1242, V1253, V1265,
F1273, V1275, V1292, Y1312, V1314, Y1316, H1324, V1326, V1328, V1342, V1353, F1371, V1373, A1378, V1407, Y1409,
Y1417, V1419, I1421, I1428, V1435, V1437, V1446, V1457, V1467, A1472, V1481, V1503, V1515, V1517, Y1519,
V1524, I1531, V1533, V1542, I1554, A1556, F1562, I1564, A1566, A1569, I1578, V1600, Y1602, Y1610, I1612,
I1614, Y1616, I1621, I1628, A1630, A1636, C1639, I1666, V1668, A1673, V1678, V1682, I1704, A1708, Y1714, I1716,
I1718, I1725, V1732, A1734, V1793, V1802, I1822, V1824, H1834, M1836, I1838, I1845, V1862, F1880, I1882, V1916,
Y1918, Y1926, I1928, V1930, F1932, I1937, A1944, I1946, I2003, F2005, H2013, V2015, V2017, V2033, A2041,
V2044, V2064, V2098, Y2100, Y2108, I2110, I2112, F2114, V2126, V2128, V2254, Y2274, V2276, H2286, V2288,
V2290, V2306, V2317, F2335, I2337, V2371, Y2373, V2375, Y2381, V2383, I2385, I2392, V2399, V2401, A2402,
A2408, L2411, L2421, V2431, L2433, A2436, I2440, V2444, I2466, H2476, I2478, V2480, F2482, I2494, V2508,
L2515, F2526, V2528, A2533, V2561, Y2563, A2567, Y2571, I2573, I2575, Y2577, I2583, A2590, A2635, V2638,
A2648, V2658, C2660, A2663, V2694, Y2696, V2698, L2706, V2708, W2710, V2715, V2722
698 UDP-glucose 4-epimerase Q14376 V5, L6, V7, H17, V19, L20, L22, V30, V31, I32, L49, V52, V60, A72, L73, L76, F82, A84, V85, I86, H87, Y104, L115,
(EC 5.1.3.2) I118, M119, V124, L127, V128, F129, A133, V135, Y136, L144, H148, I164, I168, W178, A180, V181, L182, L183,
A191, I197, M209, V212, V225, I242, H243, V244, L247, A248, H251, A253, A254, L255, L258, Y267, L269, M280, V281,
A283, M284, A309, L313, A314, L318, W320, M329, C330
699 Semaphorin-3A Q14563 I110, L308, V373, I451, V475, L476, L494, L529
700 Inositol 1,4,5-trisphosphate Q14571 L9, I11, V15, A19, I27, C37, V38, V39, Y66, V115, L123, H125, L132, A146, F161, I176, L193, V209, W218, L242, H244,
receptor type 2 C253, L264, A280, W282, I284, H307, A315, A316, L354, F367, H391, V398, I417, F429, A448, L452, L476, V483,
I514, V518, C556, H562
701 Inositol 1,4,5-trisphosphate Q14573 L8, I10, V14, A18, I26, C36, V37, V38, Y65, V116, L124, H126, L133, A147, L162, V177, L194, V210, W219, L243,
receptor type 3 H245, C254, L265, A281, W283, V285, H308, A316, A317, L354, F367, H391, I398, L417, F429, A448, L452, L476,
V483, I514, V518, C556, H562
702 ATP-sensitive inward Q14654 L149, L233, L255, L287
rectifier potassium channel
11
703 Metabotropic glutamate Q14833 L83, L86, A328, V341, L353, A363
receptor 4
704 Transmembrane Q14956 L274, I279, W283, F285, V293, V299, Y303, F309, A317
glycoprotein NMB
705 Importin subunit beta-1 Q14974 I6, L7, A21, L25, L40, L44, A53, A56, A57, L59, I61, L65, W80, V91, V95, A109, C112, V113, A114, I116, A117, L129,
L133, V137, L151, A153, I157, I161, L166, I173, A176, I177, I178, V190, A194, A197, L198, L202, F209, I218, M219,
V221, V222, V233, A236, A237, L241, I244, M245, M252, L260, A267, M268, V275, A276, I280, F282, W283, V286,
C287, A300, A301, A315, A318, L319, L322, V323, L326, L330, C345, A347, A348, C351, L352, L355, A356, I363,
V367, A385, A386, V387, A389, C392, I393, L394, L402, V406, L413, V424, A428, A429, V432, I435, C436, L439,
A442, A443, L452, C455, L456, L460, A467, V470, C471, A473, F474, L477, A478, A481, L499, F503, I506, V507, L510,
L524, A528, Y529, L532, M533, I535, V536, A540, C543, A546, V547, I554, L558, V561, L562, L584, C585, L588,
V591, L592, V595, A600, I603, V607, M608, L611, M614, F615, V624, A628, L629, A631, V632, L635, V636, L639, F643,
M647, F650, L658, V666, C667, A670, V671, L673, V674, L677, C678, L681, M693, L696, V709, I713, L714, V716,
F717, I720, A721, F728, V735, L736, L739, A742, L758, C765, L766, A768, Y769, I772, V773, L776, V787, V790,
V794, I797, L798, F800, I801, I804, V814, V815, A816, A818, A819, L821, I822, L825, A828, V833, V837, I843, L846,
L847, A858, L861, A862, A865
706 Arf-GAP with coiled-coil, Q15027 V411, C421, C423, A431, V437, L439, C443, H447, L472, M473, I481, I484, I510, L575, M588, A591, A593, A614,
ANK repeat and PH domain- A622, C623, L626, A647, L655, A656, F659, A680, I688, L691, L713
containing protein 1
707 Lysine--tRNA ligase (EC Q15046 I84, L105, F108, V128, I132, Y145, L147, L154, V156, A158, L176, I182, V184, I198, I199, L232, V240, I250, I254,
6.1.1.6) L258, F263, I266, I274, I298, H304, V308, V315, Y316, I318, C338, F340, L350, M357, V358, M361, V362, V385, F387,
F391, I394, M396, V397, L400, F414, L423, C427, L443, L444, L447, V448, L452, C456, F461, I462, H465, L472, A473,
F486, L488, F489, V490, M491, C496, A498, L502, L511, F533, C534, A545, W547, M549, I551, V554, A555, M556, F557, V567
708 Advanced glycosylation end Q15109 L36, W51, L53, W72, A76, L84, L86, V89, F97, C99, A101, V115, V117, L133, V141, C144, W157, L192, C208, F210,
product-specific receptor L214, V238, L257, W271, C301
709 Programmed cell death Q15116 A50, F52, C54, F56, L65, W67, A80, A81, F106, M108, V110, A113, Y121, C123, A125, A140, L142, V144
protein 1
710 Plectin Q15149 F185, W188, V189, L193, A196, L203, L207, L213, I214, L216, L217, V240, A243, L244, L247, L254, I262, A263, L271,
L273, I274, I277, I278, I283, I286, L301, W304, V309, C317, F320, W324, L329, F330, A332, I333, I334, L341, V347,
L353, L356, A359, F360, A363, V369, L372, L373, V378, I388, I389, Y391, V392, L395, Y396, Y421, V425, L428, M432,
I451, L483, V503, L510, L521, C545, L549, A552, L556, V575, L579, A582, L589, V593, L596, V611, L618, L662,
L665, W668, V669, V688, I702, F705, A712, Y727, L731, L734, L741, L752, L755, F758, V759, A762, L769, L798,
A826, V830, L837, M844, L847, C850, I851, H854, F864, A871, L875, L918, L921, A925, L931, L946, C950, V988,
V991, C992, F993, V995, A1002, V1006, L1009, A4418, I4420, I4431, A4434, L4448, L4449, A4453, C4454, I4458,
I4459, V4469, A4472, I4486, A4489, A4492, A4507, A4508, A4510, A4520, F4524, L4525, A4548, L4562, A4567,
L4572, A4586, L4600, A4603
711 Nectin-1 Q15223 L49, C51, V65, W67, V78, A79, Y93, I109, L111, Y122, C124, F126, L138, V142, L168, A170, C172, L213, A219, L224,
C226, I227, V228, L239, V243, L267, C269, L300, F302, Y314, C316, A318
712 Receptor-type tyrosine- Q15262 Y77, M78, V80, A91, L93, L95, H104, F108, L123, I125, V127, I138, A152, L154, A155, V156, Y164, V166, F168, A170,
protein phosphatase kappa I180, A181, I182, F214, C216, L230, A253, F255, Y268, C270, V271, V280, A284, L308, I310, L312, V328, I361,
L365, I406, V408, C420, I427, V454, V463, L465, M467, L469, I507, L509, Y524, I526, F558, Y567, F569, I571, A573
713 Receptor tyrosine-protein Q15303 Y53, C56, V58, V59, L63, I65, I68, L77, V80, V83, V87, L88, V89, A90, F94, L97, L99, L102, I104, I105, A116, A118,
kinase erbB-4 (EC 2.7.10.1) I119, L131, L134, L136, L139, I142, V147, V149, A158, I166, V167, C197, C234, A235, A248, C258, V298, C334, I337,
V348, I353, F356, C359, I362, L366, F368, L389, F392, V395, I398, L402, I404, F414, V416, F417, L420, I423, L434,
I436, I442, L445, F447, L450, I453, I458, I460, L466, C467, L477, C496, C507, C512, W513, C532, V748, I750, A769,
A773, M775, L780, V786, C787, V795, L804, V808, L820, L821, W823, C824, I827, A828, M831, L834, H841, L844, A845,
A846, V849, V851, V857, I859, L864, A888, C891, V903, W904, Y906, V908, I910, L913, M914, I929, L933, L939,
V949, M953, C956, W957, F967, L970, F974, M977, L985
714 Sonic hedgehog protein Q15465 A58, A94, M98, C102, L106, L109, A110, V113, L122, V124, W128, L139, H140, A145, V146, I148, M160, L161, A162,
A165, V173, I181, C183, V185, A187, A193
715 Transforming growth factor- Q15582 V505, M506, L509, F515, L518, A521, I522, L531, V539, F540, A541, A546, L565, H572, I573, L589, L597, V599, V606,
beta-induced protein ig-h3 V608, V624, V625, H626, V627, I628, L632
716 Myosin light chain kinase, Q15746 M1536, I1688, L1714
smooth muscle
717 Neuronal acetylcholine Q15822 A163, H164, A177, I211, L213, V286, I314, V349
receptor subunit alpha-2
718 Serine/threonine-protein Q15831 V77, L80, M127, V128, M139, L140, A153, F157, I161, L164, L167, I172, V173, H174, I177, L182, L190, I192, C210,
kinase STK11 (EC 2.7.11.1) V236, W239, A241, V243, L245, F255, I267, L285, L286, M289, I303
719 Syntaxin-binding protein 2 Q15833 L6, V10, I14, V18, I19, V22, V30, L31, I32, M33, I40, L41, I50, I57, I61, A73, I74, Y75, L77, V84, L87, F91, Y99, A102,
I104, F105, F106, L114, L118, L123, L135, A136, F137, V144, F145, L147, A149, L169, L172, A173, I176, A177, L179,
C180, A188, I189, L201, A202, V205, L209, L230, L231, I232, M233, A236, A237, V240, L243, L247, F249, M252, A253,
L291, V299, V303, L326, H346, H348, L349, A350, C353, V361, L364, C365, L371, L388, I389, V392, L393, L394,
I404, V406, L407, L408, L409, Y410, I411, L412, L422, L425, I426, A429, L437, I438, L441, L444, V448, M466, I479,
V482, M483, A486, L534, I535, V536, Y537, V538, M539, V542, M544, M547, A549, A550, V553, V563, L564, I565,
H569, L571, F576, L577, L580, L583
720 Adiponectin Q15848 A6, L13, P25, V27, L29, G34, G38, I74, P76, I97, A114, F115, V117, F132, F150, L157, Y158, F160, A161, Y162, V166,
V171, V173, L175, L183, V201, L202, L203, L205, V211, L213, F234, F237, L238
721 NT-3 growth factor receptor Q16288 I71, L134, L157, L182, A298, V301
(EC 2.7.10.1)
722 Solute carrier family 15 Q16348 I653, V660
member 2
723 Acid-sensing ion channel 2 Q16515 F99, L117, Y190, L217, I219, L221, I248, I257, I402, L428, I432
724 Interleukin-17A Q16552 C94, C99, V121
725 Calcium/calmodulin- Q16566 C63, L74, V117, L126, F127, Y136, A141, A142, A144, V145, L149, A151, L165, L170, L181, I183, A209, V222, W225,
dependent protein kinase V227, I229, I233, L234, C236, F241, I254, W266, L271, A273, L276, V277, L280, A294, W299, L317, F320
type IV
726 Laminin subunit alpha-3 Q16787 L272
121 Receptor-type tyrosine- Q16827 L920, F923, M930, F938, F942, L945, A957, Y974, V979, Y992, A995, I998, Y1007, I1008, A1009, F1021, W1022,
protein phosphatase O M1024, V1025, I1032, I1033, V1034, M1035, L1036, C1047, Y1050, V1065, F1081, I1083, V1092, H1094, Y1097,
W1100, I1114, F1117, V1118, V1121, M1132, I1133, I1134, H1135, C1136, V1140, F1146, I1147, A1148, L1149,
L1152, V1162, I1164, L1165, V1168, M1171, M1178, V1179, Y1185, F1187, I1188, C1191, V1192
728 Toxin B (EC 2.4.1.—)/strain Q189K3 L562, I578, Y580, I581, V582, A594, F598, A599, V606, L607, F608, A618, L648, F650, F663, L671, I675, I686, I693,
630 (Clostridium difficile) L695, M700, F701, Y711, L715, L716, V719, I723, M727, I735, V737, A739, I762, I778
729 Toxin A (EC 2.4.1.—)/strain Q189K5 L9, A13, Y23, I26, L30, L48, L51, I55, F58, L71, L74, I78, V82, L97, H98, F99, V106, Y113, W117, L128, W129, A134,
630 (Clostridium difficile) F135, L136, A152, F170, Y171, M175, I178, I204, I205, L209, I231, I239, L244, Y254, L258, A266, A267, V271, A275,
L276, V282, L284, M288, L289, I314, L316, A318, I319, F334, F345, I349, I358, F359, V367, L370, I372, I374, A375,
A385, L386, I387, L394, V398, Y406, L409, L413, A416, F430, L434, L446, I449, F457, A461, L467, A472, Y473, A476,
Y477, F480, L483, L497, A526
730 Protein Dok-7 Q18PE1 V7
731 Spike glycoprotein Q1HLC5 Y60, M70, L78, F83, F91, F96, A97, V99, F114, A116, I117, I119, F123, V130, V131, L147, I149, V151, C152, M156,
C157, H161, I163, L200, H203, F204, F211, A213, F224, Y238, V239, L240, L242, C244, Y252, Y262, L264, C278, A520
732 Lipoprotein, Lp Q1HP67 W1640, C1665, C1676
733 Endogenous retrovirus group Q1PHM6 A54, F92, M94, M99, M103, I107, V119, V126, M145, L156, A220, I221, C235, V266, I281, L284, V288, I321, C326, I328,
K member 113 Env L337, V340, V341, I353, Y378, C379, F385, C417, I422, I423, V429, A432, M433, L452, L453, I469, F470, W481, L485,
polyprotein V491, I493, V507, I550, V551, L557, L558, A560, I561, A563, M567, L568, V572, I575, L578, V582, I637, I644
734 CTLA-4 protein Q28090 A52, V67, V71, C101, V110, C127, V129, I147
735 Hemagglutinin [Cleaved Q289M7 V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, V74, A75, W77, I78, L79, C84, L87,
into: Hemagglutinin HA1 W93, Y95, I96, V97, Y108, L118, L122, V125, F128, F134, A150, C152, H154, L164, L165, L167, L173, L177, V189,
chain; Hemagglutinin HA2 L190, V191, L192, W193, V195, H196, H197, Y208, Y214, V215, V217, V218, I243, Y245, Y246, L249, L250, I256,
chain]/strain A/New F258, A260, L264, I265, A266, Y269, A270, F271, A272, L273, F277, I281, I282, C291, C295, A301, I302, H312,
Zealand: South M330, V331, A348, Y365, A387, I388, L461, L469, H485, C487, C491
Canterbury/35/2000 H1N1
736 HLA class II Q29974 F36, L37, F46, F47, V53, F55, L56, Y59, V67, F69, Y76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145,
histocompatibility antigen, C146, V148, F151, W160, M171, L190, V199, Y200, C202, V204
DRB1-16 beta chain
737 MHC class I polypeptide- Q29980 L28, L32, V34, F45, L51, F56, L57, Y59, A66, A73, L96, L100, L113, C119, F133, F140, L141, L145, A158, A162, V165,
related sequence B L191, Y194, V223, C225, A227, F230, W239, V268, I272, C282
738 MHC class I polypeptide- Q29983 L28, V34, V49, L51, F56, C59, C64, A73, L96, L100, L113, C119, F133, F140, L141, A162, V165, L191, I221, V223,
related sequence A C225, A227, F230, W239, V268, I272, C282
739 Kinesin-like protein KIF7 Q2M1P5 V18, A19, L20, V47, L49, V70, Y71, V75, A88, V90, F91, A92, M104, I119, V120, A123, V143, Y145, L146, V148, F153,
L156, V192, V220, F221, V223, L225, F248, F250, V251, A281, L282, V285, I286, A288, I306, I309, L310, L314,
A318, M322, I323, A324, C325, V326, L340, A343
740 Endogenous retrovirus group Q2N0S5 A54, A69, M94, M99, V100, M103, L121, L124, L128, L145, C148, M152, F167, L192, A203, C217, A218, A223, I224,
K member 24 Env L225, C238, V241, L258, V269, F287, V291, I293, F314, A316, I324, C329, V331, L340, V343, V344, L347, I357,
polyprotein F381, C383, F389, L413, C415, I420, I421, I427, A430, M431, Y432, A433, I446, L449, I450, L451, F465, W476,
L480, V486, I488, V502, I545, V546, L552, L553, A555, I556, A558, L562, L563, V567, I570, L573, V577, I632, I639
741 Endogenous retrovirus group Q2N0S6 W44, F52, C53, A54, W68, A69, F92, M94, W95, M99, V100, M103, L110, C118, V119, L121, L124, C125, L128, C130,
K member 8 Env L145, C148, F150, M152, Y164, F167, L192, C195, I200, A203, C204, C217, A218, A223, I224, L225, C227, C238, V241,
polyprotein I250, L258, V269, V285, F287, V291, I293, C295, F314, A316, I324, C329, V331, W336, L340, V343, V344, L347,
I357, F359, H372, C376, F381, Y382, C383, L388, F389, L413, C415, I417, I420, I421, I427, A430, M431, Y432, A433,
C442, I446, L449, L451, F465, W476, L480, Y483, V486, I488, A494, V502, I545, V546, L552, L553, A555, I556, A558,
L562, L563, V567, I570, L573, V577, I632, I639
742 HLA class II Q30154 F36, L37, F46, F47, V53, F55, L56, L67, F69, Y76, W90, L97, A103, C108, V120, V128, L138, L143, L144, V145, C146,
histocompatibility antigen, V148, F151, W160, V171, L190, V199, Y200, C202, V204
DR beta 5 chain
743 Hereditary hemochromatosis Q30201 L30, Y32, A49, V53, F58, V59, Y61, L87, L91, I105, L118, L122, C124, H145, L146, A162, A176, L183, C187, L191,
protein L223, C225, A227, Y230, W239, I268, V272, C282, V284
744 Genome polyprotein Q32ZE1 I291, C293, V311, V313, V314, L315, C320, V321, V323, M324, A325, V331, I333, L335, V340, Y349, C350, Y351,
[Cleaved into: Protein A370, V381, C395, L403, V404, C406, A407, F409, M415, I420, L425, Y427, I429, M430, L431, V433, V455, A464,
C/strain Mr 766 (ZIKV) L466, L472, L474, C476, L482, Y488, Y489, L490, M492, H496, W497, V499, F504, H512, L528, V529, V541, L555,
H574, L575, C577, L579, M581, L584, C594, F598, V612, V614, V616, Y618, C625, I627, M631, A632, L644, I645,
I651, M660, L662, L664, I673, V674, I675, I811, V978, I1008, V1536, M1539, H1545, M1547, V1570, L1574, V1575,
Y1577, W1581, V1593, L1595, A1597, V1598, I1613, A1623, V1624, I1637, I1645, L1647, Y1648, V1653, V1660,
L1703, I1706, V1707, A1710, V1718, I1719, L1720, A1721, V1726, A1727, M1730, L1734, V1756, L1758, M1759,
H1761, F1764, Y1777, L1779, I1781, M1782, A1785, I1793, A1794, A1795, I1799, A1808, A1809, A1810, I1811,
F1812, M1813, V1850, V1858, W1859, F1860, V1861, I1870, A1871, C1873, L1874, A1877, I1882, L1884, F1889,
W1901, F1903, V1904, I1905, A1914, V1921, I1922, V1938, V1946, A1949, A1951, A1952, I1958, Y1969, M1970, A1976,
A1983, A1988, L1991, L1992, I1995, L1997, A2003, L2005, F2030, V2031, L2033, L2039, W2042, L2043, A2044, V2047,
A2048, W2059, C2060, I2069, V2078, L2088, A2095, F2107, F2110, A2111, W2528, Y2543, I2548, V2551, A2556,
A2559, L2560, A2570, V2571, A2576, I2578, L2581, L2587, V2593, V2594, L2596, C2598, A2607, A2608, V2613,
V2616, Y2619, V2648, C2656, L2659, L2660, C2661, V2672, L2678, V2680, L2681, V2684, W2687, L2688, F2695,
C2696, I2697, V2699, L2700, C2701, Y2703, M2707, M2711, L2714, L2722, V2725, H2733, M2735, Y2736, W2737,
V2738, I2745, V2749, L2755, L2756, I2794, I2801, V2842, L2845, W2849, V2880, V2890, M2891, L2898, I2929, A2939,
A2942, F2948, C2964, C2967, V2968, Y2969, M2994, L2996, A2998, L3001, A3005, F3008, L3009, W3014, M3015,
V3024, L3032, Y3034, L3036, M3039, A3042, M3047, I3059, A3082, V3085, Y3090, V3094, V3095, V3097, V3107,
I3110, I3111, V3123, A3126, L3127, F3130, L3133, V3134, V3135, L3137, I3138, M3141, M3149, L3152, V3161,
L3165, L3173, M3176, A3177, V3178, V3184, V3185, F3192, A3195, L3196, F3198, L3199, M3202, V3224, F3226,
F3231, I3242, V3243, V3244, C3246, I3253, A3256, A3262, A3270, A3273, A3277, W3280, L3282, F3285, H3286,
L3290, M3293, A3294, A3296, I3297, A3300, V3301, V3303, H3316, L3328, W3331, V3334, W3335, H3341, I3354,
L3357, A3378, I3381, V3385, I3391, M3399, L3402
745 N-acetylglucosamine-1- Q3T906 L139, L154, F161, V191, A228, L230, L243, L251, A267, L269, L271, A300
phosphotransferase subunits
alpha/beta (EC 2.7.8.17)
746 Integrin beta-2-like protein Q3UV74 V127, L129, Y130, F131, L132, M133, V146, L149, L153, L154, L157, I166, F168, I171, F176, F189, L193, L209, A211,
V212, V213, V215, A216, I222, L231, V232, L233, Y265, L279, I291, F292, V293, V294, Y302, I309, V324, I328
747 Tyrosine-protein kinase (EC Q3ZC95 F10, L11, F30, L31, L32, L37, I61, C63, V64, V67, F98, F102, V104, Y112, V113, F114, W124, L128, A384, V427, I429,
2.7.10.2) I432, F442, A446, M450, L457, V463, C464, I470, I473, L482, L486, L498, L499, C502, V505, C506, A508, M509,
L512, H519, L522, A523, A524, C527, V529, V535, V537, Y545, V561, V568, I580, W581, F583, V585, L586, M587,
I590, Y591, I610, L616, A622, V626, I629, M630, C633, W634, F644, L647, I651, V654
748 Envelope glycoprotein Q3ZLH8 A54, H65, A69, V94, V100, M103, V119, I150, L189, C214, A220, I221, C224, C235, V238, I247, L255, I266, I280,
gp160 I281, V282, L284, V288, I290, A293, I321, C326, V328, W333, L337, V340, A341, I342, L344, I352, I353, F354, H367,
C371, F376, C378, L383, F384, L407, C409, I411, I414, I415, V421, A424, M425, I440, L444, L445, F462, W473, L477,
V483, I485, V499, I542, V543, L549, L550, A552, I553, A555, L559, L560, V564, I567, L570, V574, I629, I636
749 Cytotoxin L Q46342 L9, V13, Y24, I27, L31, Y46, L49, I52, Y59, L72, F75, L79, V83, L98, H99, F100, Y114, W118, V129, A135, L137, I138,
L141, I145, A149, F171, M176, I179, F186, I206, L210, L254, L259, V260, A267, A268, I274, L277, V283, Y284, L285,
I289, L290, L317, A319, I320, F335, F346, I359, F360, L363, V368, L371, V373, I375, A376, A386, L387, I388, C395,
V399, I403, Y407, L410, F431, I450, L454, F458, L468, V473, Y474, A477, Y478, L481, F501, A527
750 Envelope glycoprotein Q49DS8 I13, V15, L17, V21, I23, I53, C58, I60, L69, V72, A74, L76, I84, V85, H99, F108, C110, L115, F116, I127, L129, C131,
I136, I137, V143, A146, M147, I162, L165, L166, L167, F181, W192, L196, V202, I204
751 Cell adhesion molecule- Q4KMG0 V737, V739, W741, F754, V756, V782, Y791, F793, V795, A797, V815, I832, I843, L845, F862, I864, I891, Y900, I902,
related/down-regulated by M904, C906
oncogenes
752 Cordon-bleu protein-like 1 Q53SF7 V187, I189, L207, L210, I214, C215, L227, L228, L251, A253
753 Receptor protein-tyrosine Q59FL8 I611, V613, I615, A634, M637, V640, V645, C646, I651, L659, I660, L669, V673, L685, L686, W688, C689, I692, A693,
kinase (EC 2.7.10.1) L699, V705, H706, L709, A710, A711, V714, V716, V722, I724, F727, A753, V768, Y771, V773, V775, L778, I794,
L798, L804, V814, M818, C821, W822, F832, L835, F839, M842, L850
754 Integrin beta Q59H50 C81, C88, C91, C107, L113
755 Filaggrin-2 Q5D862 L33
756 Guanine nucleotide-binding Q5JWF2 L686, L687, L688, L689, I699, M703, I738, L742, A745, I746, I749, L756, I774, F789, A793, L796, V802, C805, C817,
protein G A818, F821, I825, I828, F862, M864, V867, A886, I887, F889, V890, V891, Y896, F916, L925, V930, I931, L932, L934,
L939, L940, V944, A980, I984, F988, A994, I1015, C1022, I1026, H1030
757 MAGUK p55 subfamily Q5T2T1 A73, L96, L108, V164, A173, L185, V188, I201, I212, F214
member 7
758 Dyslexia-associated protein Q5VV43 L354, A356, W372, L393, L395, Y403, F405, V407, V409, V422, V424, A629, L644, W660, A679, V681, L684, F691,
KIAA0319 L693, V695, V709
759 Disabled homolog 2- Q5VWQ8 L653
interacting protein
760 Renalase (EC 1.6.3.5) Q5VYX0 L5, I6, A9, L15, C16, A17, A31, V32, W33, A56, L58, L80, V106, A107, I111, I114, I115, I135, W142, V144, F154, I157,
V158, L159, V163, I166, I173, L185, Y194, A195, L198, F199, I221, V224, V243, V262, V266, F311, L312, A313,
C314, F319, I328, A331, V334
761 Hemagglutinin [Cleaved Q67333 I7, I18, C19, I20, Y22, A24, V31, I34, V41, I47, L48, L56, C57, L59, L65, L67, C70, I72, A73, W75, L76, L77, C82, L85,
into: Hemagglutinin HA1 W91, Y93, I94, M95, Y106, L116, L119, L120, V123, F126, L132, A148, C149, V151, M161, V162, W163, L164, A174,
chain; Hemagglutinin HA2 M186, L187, I188, I189, W190, V192, H193, H194, Y205, Y211, V212, V214, L219, L236, M240, F242, L246, L247,
chain]/strain I253, F255, L261, I262, A263, Y266, F268, I270, I278, M279, C288, C292, A298, I299, H306, H309, I313, V320, L325,
A/Singapore/1/1957 H2N2 L327, A328, L331, A345, M357, Y362, A384, F385, A436, L448, H451, V455, L458, V462, L466, C477, H482, C484,
C488, M489
762 Envelope glycoprotein Q69994 A52, H63, A67, M92, M97, V98, M101, W109, V117, V124, I172, Y239, C240, A246, I247, C250, C261, V264, I273,
gp160 L281, L282, V292, I306, I307, I308, L310, V314, I316, C318, I346, C351, I353, W358, L362, I365, V366, A367, L369,
I378, V379, F380, H393, F395, F402, C404, L409, F410, L430, C432, I434, I437, I438, V444, A447, M448, I463, L466,
L467, L468, I483, F484, W495, L499, V505, I507, V521, I565, V566, L572, L573, A575, I576, A578, L582, L583, V587,
I590, L593, V597, I652, I659
763 Hemagglutinin/A/Viet Q6DQ33 F8, I19, C20, I21, A25, V32, I35, V42, I48, L49, L57, C58, L60, L66, L68, C71, V73, A74, W76, L77, L78, C83, F86, W92,
Nam/1203/2004(H5N1) Y94, I95, V96, A99, C106, Y107, L117, L120, L121, I124, F127, I133, A150, C151, Y153, V163, V164, W165, L166,
I167, I176, L188, L189, V190, L191, W192, I194, H195, H196, A201, Y207, Y213, I214, V216, L221, M242, F244, F245,
I248, L249, I255, F257, F263, I264, A265, Y268, A269, Y270, I272, I280, M281, C290, C294, A300, I301, H308, H311,
I315, V322, L327, L329, A330, A351, M363, Y368, A390, I391, A442, L454, V461, L464, V468, L472, C483, H488,
C490, C494, M495, A512
764 Tau-tubulin kinase 2 (EC Q6IQ55 V17, V23, Y36, A38, V47, L49, V51, V67, L68, L71, C78, V92, V93, L101, L119, L121, I125, L126, I129, I132, H139,
2.7.11.1) F147, C159, M161, L209, L212, F213, Y214, M215, L216, F219, W226, V235, F255, F258, I262, L276, V279, F280,
I284
765 Growth/differentiation factor Q6KF10 F363, C387, A401, I430, C452, C454
6
766 Iodotyrosine deiodinase 1 Q6PHW0 I116, A123, I149, I181, A188, I190, L191, I192, L193, I194, F195
767 Spike glycoprotein/HCoV- Q6Q1S2 I485, F487, A489, A491, L509, W541, C577, F579, L581, A583, L596, V598
NL63
768 Nucleoprotein/strain Q6TXC0 V33, I36, F39, M43, L56, I57, I63, M66, V67, L68, A70, I96, I116, I119, W120, M136, M137, W139, A153, L154, M163,
A/Equine/Santiago/1/1985H3N8 M189, V190, L193, I194, I197, I201, Y219, C223, L226, F230, A234, M238, M239, V242, L256, L259, A263, I265,
L266, C275, L276, A278, Y281, F291, Y296, L307, I312, L315, L328, V329, W330, M331, A332, C333, H334, A336,
A337, L341, I347, V352, V363, M371, L381, A387, A427, A428, I444, Y487
769 Hemagglutinin/ Q6VMK1 V58, I66, C67, L76, C79, L81, L82, I85, C91, A99, L101, I102, I103, C112, L123, L127, I133, I145, C154, Y162, M165,
A/Netherlands/219/2003 L168, Y184, A192, L193, I194, I195, W196, I198, H199, Y211, I218, V220, I246, F248, L253, V259, F261, F263, A266,
(H7N7) F267, I268, A269, P270, A273, F275, L276, I283, C293, C297, Y298, A353, Y370, A392, L466, L474, H490, C492, C496,
A514
770 Neuraminidase (EC Q6XV28 L87, V94, A105, I106, I114, V116, Y121, L122, C124, M131, F132, A133, L134, A145, L158, I159, W161, C176, I177,
3.2.1.18)/strain C184, M191, I193, C194, M195, A202, A204, V205, V206, Y208, A220, L224, C231, V232, C233, V240, V241, M242,
A/Budgerigar/Hokkaido/1/1977 I255, I256, Y257, F258, I276, C279, C281, Y282, V285, I288, C290, I291, C292, A299, V303, I304, I306, Y317, L318,
H4N6 C319, V322, L323, V350, F353, A354, F355, W362, L363, Y375, M377, L378, V380, A383, I397, I398, A409, F410, I411,
F420, F424, Y425, V426, L428, V438, I445, V446, A447, L448, A464, I466
771 Tubulin alpha-1A chain Q71U36 C4, I5, I7, H8, V9, V14, I16, C20, W21, L23, Y24, C25, H28, I30, F52, F53, V62, A65, V66, F67, V68, L70, V74, I75, V78,
L86, I93, A99, A100, Y103, A104, I115, V118, L119, I122, L125, F135, L136, V137, F138, H139, L153, M154, L157,
L167, F169, Y172, A174, Y185, I188, L189, L195, C200, A201, F202, M203, V204, A208, I209, I212, C213, L227, L230,
I231, I234, V235, I238, A240, L242, V250, L252, F255, L259, V260, I265, H266, F267, L269, A270, A273, V288, I291,
C295, M302, V303, C305, Y312, M313, C315, C316, L317, L318, Y319, V323, V328, A331, I335, V344, I355, V363,
A369, A374, V375, C376, M377, L378, A383, I384, A387, W388, L391, F395, Y399, Y408, F418, A421, M425, L428,
Y432
772 Endogenous retrovirus group Q75760 A54, A69, M94, M99, V100, M103, I107, V119, L121, V126, I151, C154, A171, L190, A221, I222, C225, C236, L256,
K member 9 Env L257, V267, I281, I282, V283, L285, V289, I291, C293, F312, I322, A325, C327, I329, W334, L338, I341, V342, I343,
polyprotein L345, I354, V355, F356, H369, F371, C373, F378, C380, L385, F386, L407, C409, I411, I414, I415, V421, A424, M425,
I440, L443, L444, L445, I458, F459, W470, L474, Y477, V480, I482, V496, I539, V540, L546, L547, A549, I550, A552,
M556, L557, V561, I564, L567, V571, I626, I633
773 Rho-related GTP-binding Q7L0Q8 V50, C52, V53, L54, V55, V60, L65, V66, Y74, A82, V90, V92, V97, L99, L101, A105, Y118, I123, F124, L125, L126,
protein RhoU C127, F128, V130, F136, V139, W143, V144, I147, C151, I156, I157, L158, V159, L175, V183, A188, L190, C191,
A192, I195, C203, L211, V214, F215, A217, A218, I219
774 Ribonucleoside-diphosphate Q7LG56 L34, I52, A66, W78, F88, I89, I92, L93, A94, F95, F96, F111, V115, V117, A120, F123, Y124, H134, M137, L141, I142,
reductase subunit M2 B (EC Y145, I146, A158, I159, Y164, A169, W171, V187, V188, A189, A191, A192, V196, F197, F198, A203, A204, I205,
1.17.4.1) L208, L213, M214, L217, I224, F234, A235, C236, M238, F239, V251, I254, I255, A258, V259, F265, L266, A269, L270,
V272, L274, I275, M282, I286, A290, L294, F303
775 Ankyrin repeat and sterile Q7Z6G8 V815, W818, L819, L831, F836, M842, M847, L852, I857, I866, A869, I870, V889, L893, F905, I933, I939, A1064,
alpha motif domain- F1065, A1084, C1085, I1105, L1107, V1109, V1114, I1130, I1133, F1146, A1147, Y1148, I1149, C1160, V1162,
containing protein 1B F1163, A1171, I1174, L1178, A1181
776 E3 ubiquitin-protein ligase Q7Z6Z7 A1335, A1338, A1348, L1352, F4001, V4019, V4021, V4026, F4027, L4034, M4042, W4065, Y4066, I4069, M4073,
HUWE1 (EC 6.3.2.—) L4080, I4093, F4107, F4109, V4110, I4113, V4114, A4115, A4117, L4124, C4126, F4128, F4132, Y4133, I4136,
M4146, F4174, V4207, V4210, C4211, M4215, F4226, F4230, I4234, L4238, I4239, I4241, L4247, I4251, I4278, F4281,
A4284, L4285, A4294, V4300, F4311, F4323, I4325, C4341, L4345, L4347, Y4350, L4356, L4360, A4363, I4364
777 Hemagglutinin [Cleaved Q82559 A26, L28, C29, L30, A34, V41, V51, L57, V58, I66, C67, V73, C79, L81, I82, M85, L86, C91, F94, L101, F102, I103, F109,
into: Hemagglutinin HA1 C112, Y113, Y115, Y120, A121, L123, V127, A128, L133, F140, A153, C154, F162, F163, L166, L169, L179, Y193,
chain; Hemagglutinin HA2 W195, I197, H198, H199, Y210, V217, V219, I245, I247, Y248, I251, V252, I257, L258, I260, L266, V267, A268, F273,
chain]/strain I289, C296, I297, I303, I324, L331, A332, A349, W358, Y366, A388, A440, L462, L470, C481, F482, I484, H486, C488,
A/Equine/Kentucky/1/1981 C492, I493, I496, A510
778 Fusion glycoprotein F0 Q84850 I233, F237, V247, M251, L257, I261, M274, V281, F342, V349, C382, A412, V414, C416, C422, A424, V450
779 Regulating synaptic Q86UR5 V600, L602, A614, L616, L618, A633, I635, A644, L650, V656, W659, L664, V672, I676, V685, I687, V689, L746,
membrane exocytosis V748, L750, L759, V761, V763, A766, V782, M784, V818, F823, L828, I830, V832, L846, I849, L853
protein 1
780 Fermitin family homolog 3 Q86UX7 L73, L74, I358, V378, F380, L404, I422, V426, L437, C439, A446, W448, M449, A450, C452, L454, A455
781 Transmembrane protease Q8IU80 I504
serine 6 (EC 3.4.21.—)
782 Sodium channel subunit Q8IWT1 L51, C53, L64, W68, L79, I80, V84, I101, I114, I116, L118, L121, C131, V133, L149
beta-4
783 Interferon lambda-3 Q8IZI9 L27, L45, A59, L65, L75, L82, L85, A93, L94, A96, L98, L102, L126, C136, A161, C169, V174, L181
784 Interferon lambda-2 Q8IZJ0 L31, L49, A63, L69, L89, A100, L106, C140
785 Abl interactor 1 Q8IZP0 V451, A453, L465, I473, V475, I476, C488, F495
786 Kin of IRRE-like protein 3 Q8IZU9 I438, C440, I442, A452, W453, L483, I485, I488, Y497, C499, A501, L514
787 Envelope glycoprotein Q8J581 C50, A51, H62, A66, M91, M96, V97, M100, I104, L107, V116, L143, I210, Y212, C213, A219, I220, C223, C234, V237,
gp160 I246, L254, I265, I267, I279, I280, V281, L283, V287, I289, C291, I320, A323, C325, V327, W332, L336, V339, A340,
L343, I351, I352, H366, F375, C377, F383, L408, C410, I412, I415, I416, A422, A425, M426, I441, L444, L445, L446,
F460, W471, L475, Y478, V481, I483, V497, I540, V541, L547, L548, A550, I551, A553, L557, L558, V562, I565, L568,
V572, I627, I634
788 Endogenous retrovirus group Q8JDI3 A54, H65, A69, F92, M94, M99, V100, M103, I107, L110, V126, I145, M152, V173, I175, L189, F206, I211, Y213, C214,
K member 21 Env A220, I221, C235, V238, I247, L255, V266, I280, I281, V282, L284, V288, I290, I321, C326, V328, L337, V340, V341,
polyprotein L344, I352, F354, H367, F369, C371, F376, C378, F384, L405, C407, I409, I412, I413, V419, A422, M423, I438, L441,
I442, L443, F457, M464, W468, L472, Y475, V478, I480, V494, I537, V538, L544, L545, A547, I548, A550, L554, L555,
V559, I562, L565, V569, I624, I631
789 Neuroligin-4, X-linked Q8N0W4 I55, V70, Y73, V76, Y78, F88, V109, C110, L132, C146, L147, L149, I151, V153, V168, M169, V170, I172, H173, L190,
A191, V196, I197, V198, I199, I201, Y203, I207, F210, L211, A218, L224, I228, A230, L231, W233, I234, V238, V248,
I250, F251, A257, C259, V260, L262, L263, A276, I277, I278, A288, I299, L300, A301, V304, C306, V315, L318, L326,
I338, I349, Y365, I367, M368, L369, V380, V390, V399, F402, V403, L416, I420, L440, L443, V450, A457, H460,
Y470, A471, F472, A488, V493, Y495, V496, F497, F508, L519, V523, M524, Y526, W527, F530, A531, A558, L570,
I572, A584, F589, I603
790 Jouberin Q8N157 V1057, A1058, I1072, I1078, V1080, F1101
791 Gamma-aminobutyric acid Q8N1C3 I436
receptor subunit gamma-1
792 TGF-beta-activated kinase 1 Q8N5C8 L13, L16, V27, V28, M32, C42
and MAP3K7-binding
protein 3
793 Inactive dipeptidyl peptidase Q8N608 L69, V94, V95, L117, V139, A142, A155, V158, L180, A183, L192, I193, Y194, I195, I200, L230, Y231, L235, A241,
10 L251, A252, L254, I256, I266, Y280, L294, Y295, V296, V297, L299, L306, Y320, I321, V324, V333, V334, W336,
L337, I345, C349, F385, V388, H400, V401, A402, V425, I438, F440, L452, C475, F489, L490, C493, L503, L545, L547,
L549, A562, L563, L564, L565, V576, L588, V594, I595, V596, A597, L609, I615, V622, V631, I647, Y655, A657, F668,
C670, A675, L680, A684, A686, F687, L692, V711, I721, H723, V730, F732, H734, L742, I773, F777, L781
794 Proprotein convertase Q8NBP7 V80, L82, A95, L98, A102, F122, V124, L130, A134, V140, I143, F150, I161, V180, V182, Y183, L184, L185, H193, I196,
subtilisin/kexin type 9 (EC H229, L230, A231, V233, V234, A242, A245, M247, L250, V252, I271, L283, V284, V285, L286, L287, C301, L304,
3.4.21.—) V309, V310, L311, V312, A314, A315, A322, A328, A330, V333, I334, V336, A338, V346, V359, L361, F362, A363,
I368, A371, A388, A389, A390, H391, V392, A393, I395, A396, A397, M399, L400, A409, L411, L415, I424, F429,
V441, A442, A473, A475, L484, C486, F489, C509, A511, V520, A522, I523, A524, C526, C527, A542, C588, A594,
I596, H597, A598, C600, C601, A603, L606, V622, A625, L632, C654, V656, V672, A674, A676, C678, C679
795 Cytoplasmic dynein 2 heavy Q8NCM8 L1352, F1356, F1368, C1411, L1419, L1438, M1476, V1484, V1496, L1511, L1515, W1626, C1640, M1644, Y1655,
chain 1 C1671, L1675, A1678, V1699, A1736, V1750, L1751, A1753, V1754, A1764, F1788, V1815, A1826, V1872, A1901,
L1943, A1962, V1975, V1976, I1977, V1978, W1989, L1992, A1995, M2008, I2053, V2069, F2094, A2105, I2113,
C2182, L2200, F2208, F2254, F2275, W2278, L2279, L2301, A2304, L2354, V2355, L2374, A2376, V2395, V2403,
L2427, V2474, V2476, V2480, L2524, I2526, A2531, F2548, F2572, L2634, I2640, F2646, L2651, L2653, A2654,
V2668, A2701, V2708, L2712, F2722, L2751, H2777, L2780, C2803, V2805, M2808, I2819, C2862, Y2872, F2875,
A3208, A3209, A3317, V3318, L3324, V3332, V3353, I3360, A3383, V3390, L3403, A3496, L3509, A3522, F3571, A3572,
F3575, W3648, Y3651, C3657, A3694, L3724, L3740, A3754, M3755, A3771, W3776, L3777, A3811, L3822, A3861,
A3868, F3870, H3871, A3872, C3874, Y3927, I3931, L3944, L4021, L4040, V4090, Y4140, L4141, L4144, I4151,
A4202, I4217, C4225, C4248, A4301
796 Semaphorin-6D Q8NFY4 L150, A179, Y199, I211, Y252, A256, V269, F292, L297, A407, V417, L465, C521
797 Protein CASC5 Q8NG31 F2149, Y2151, I2154, L2156, I2158, L2197, I2202, V2233, C2236, L2239, I2243, L2265, L2267, F2269, F2278,
I2280, L2282, I2309, Y2322, V2326, V2327, I2330
798 Envelope glycoprotein Q8Q7Z9 M23, I24, I30, L69, A100, I101, C115, V118, V131, L135, L136, V146, I160, I161, V162, L164, V168, I170, C172,
A192, F193, I196, M202, H206
799 CTLA4 Q8TDA6 A54, C58, Y60, V69, V71, V73, C85, L95, V112, I116, C129, V131, I149
800 2-amino-3- Q8TDX5 I5, H6, H8, I9, L10, L17, A37, L39, C53, M63, A72, L73, M79, F80, Y82, L92, C93, L96, L100, F111, L114, L117, M119,
carboxymuconate-6- A125, M129, C132, V141, I143, V147, L152, L157, V160, Y161, A163, A164, C169, L171, F172, V173, A202, I203,
semialdehyde decarboxylase M206, I207, V211, V220, C221, F222, A223, F229, F262, L274, L277, V286, I287, I305, M308, L319, A321, A324, F327
(EC 4.1.1.45)
801 Partitioning defective 3 Q8TEW8 I12, L434, I499, L509, I527, I533, L550, V553, L558, A566, I584
homolog B
802 Protein Shroom3 Q8TF72 A30, L32, A63, L70, V76, I79, A91, L102, L104, V106
803 Intelectin-1 Q8WWA0 C41, C48, L58, C70, L81, V82, A83, V85, C94, W100, A129, Y139, L147, I149, H151, V152, W161, L167, L176, L183,
I186, Y187, W200, V236, F238, V240, F241, A246, A247, A249, L250, C251, M254, H264, C265, F272, C280, F283,
F286, I303, A306, A307, L309, L310, F311, Y312
804 Palladin Q8WX93 F1020, C1022, V1024, I1032, W1034, C1058, L1060, Y1073, I1075, A1077, L1090, C1152, M1154, C1156, V1158,
L1193, I1195, V1198, Y1206, C1208, A1210, L1253, C1255, W1267, I1291, L1293, I1295, A1298, Y1306, V1308,
A1310
805 Relaxin receptor 2 Q8WXD0 C52, L59
806 Nesprin-2 Q8WXH0 A191, V203, W210, A215, F216, A218, I219, I220, L242, A245, F246, A249, V264, I274, M275, Y277, V278, A279,
F281, L282
807 Mucin-16 Q8WXI7 L14325, F14327, I14329, L14332, I14353, L14357, L14360, V14389, C14393, A14399, I14407, F14411, L14421,
V14431
808 Hemagglutinin [Cleaved Q91MA7 A27, L29, C30, L31, A35, V42, V52, L58, V59, I67, C68, I74, C80, L82, I83, A85, L86, L87, C92, F95, L102, F103, V104,
into: Hemagglutinin HA1 F110, C113, Y114, Y116, Y121, A122, L124, V128, A129, L134, F141, A154, C155, F163, F164, L167, L170, Y177, L180,
chain; Hemagglutinin HA2 L193, Y194, I195, W196, V198, H199, H200, Y211, V218, V220, I246, I248, Y249, I252, V253, V258, L259, I261,
chain]/strain A/Hong L267, I268, A269, F274, I290, C297, I298, I304, V325, L332, A333, A350, W359, Y367, A389, A441, L463, L471,
Kong/1/1968 H3N2 C482, F483, I485, H487, C489, C493, I494, I497, A511
809 Alpha-N-acetylneuraminide Q92185 W68, F78, C85, C86, F92, M105, Y107, I117, C138, A139, V140, V141, I146, L147, C152, I156, F161, V162, C165,
alpha-2,8-sialyltransferase L167, V178, L184, V185, I191, I192, L199, F206, Y213, A222, F223, L233, V235, Y236, L239, A244, F262, W263,
(EC 2.4.99.8) A270, L273, A282, A283, L284, L286, C287, V290, Y293, W296, F298, I307, Y311, Y312, L316, F321, A323, M324,
L334, L340, C347
810 Nicastrin Q92542 C50, L53, L54, C62, I73, V85, M95, V96, L98, F103, M108, L111, L121, A122, V123, W164, L171, F176, F178, I180,
F181, L182, L183, V191, I192, L212, C213, A214, M215, L217, C230, C248, L251, V256, W257, M259, V275, V276,
V277, A278, A279, L282, F288, A292, A295, A298, V299, A300, F302, V303, L306, A307, A308, A309, A311, L312,
A315, V325, M326, F327, V328, F329, F330, F335, Y337, I338, M347, V354, F362, L365, V368, L376, M378, V394,
L397, L401, F430, V439, L441, A442, L471, A484, L487, A488, V490, A491, V493, L494, L498, Y499, L501, A502,
V511, A513, V518, L521, L522, F525, A529, F534, L538, H553, I555, V566, V567, A570, L571, V605, C620, A628,
A630, A634, A658, I660
811 Protein NDRG1 Q92597 Y73, C92, A119, I145, W183, H214, L284
812 Nectin-2 Q92692 L52, C54, V68, W70, A83, F85, L103, L127, Y138, F142, L156, V180, A181, C183, V236, C238, V240, L255, V257,
V263, W272, L314, C329, V331
813 Ryanodine receptor 2 Q92736 L14, V20, V21, L22, C24, A26, L35, C36, L37, A38, A39, I64, C65, F67, L69, L78, L113, Y115, A118, I119, L121, H123,
L130, C131, A144, V147, L149, C158, W160, I162, V175, L181, L183, L192, V203, A205, A206, W212, V214, L228,
L234, L236, H238, C244, L245, V247, V260, Y262, V267, A271, L274, W275, L277, I289, F295, L297, H299, V300,
Y305, L306, L315, L316, A322, F329, F331, I354, C361, I363, L372, A391, I403, L405, A416, V418, I419, F426, F429,
L447, V452, L456, L459, I460, F463, L482, L488, F489, M494, V498, C501, I502, L505, F514, A518, I529, L530, L533,
L536, A539, L540, W697, A698, V718, C757, I766, V791, V792, A886, F921, V996, A1000, H1004, L1050, V1054, V1115,
W1117, L1128, A1134, A1136, F1137, V1162, C1164, V1166, M1173, F1175, F1195, V1204, V1443, W1445, I1446,
L1459, V1465, V1467, L1469, I1507, L1518, F1520, A1542, F2720, A2725, H2727, H2729, L2779, M2782, M2828,
M2840, M2844, A2845, A2889, I2892, L2893, L2896
814 Serine protease HTRA1 (EC Q92743 C53, C76, L132, L150, V175, I179, A182, V183, V184, H185, I186, L188, F207, I208, I215, V216, A219, V221, V222,
3.4.21.—) V228, V230, A240, A249, I251, A252, I254, I256, V279, V280, A281, I282, V297, I317, A321, I323, L332, V333, V339,
I340, I342, F353, A354, I355, I360, F363, I383, A395, L398, A412, I414, A423, L428, V433, I434, I437, V448, I452,
L458, M460, V462, I471, V473
815 Secreted frizzled-related Q92765 A63
protein 3
816 Ras-responsive element- Q92766 C701, C792, C805, C1514
binding protein 1
817 Disks large homolog 3 Q92796 I132, L134, L141, A146, V154, I160, I162, A170, A171, V179, V183, L184, V186, V191, A199, A202, L203, A206,
V210, L212, V214, V227, L229, L236, I240, I255, I257, A265, A266, L278, V281, L286, A294, L298, V305, L307,
V309, A310, I387, L389, I409, F410, V411, A420, L426, I432, V435, A448, A451, V459, I461, A463
818 X-linked retinitis Q92834 A13, V14, H46, A48, V49, V50, L56, M58, F59, L67, V81, V89, A92, H98, L100, V101, V108, A110, L119, I133, A153,
pigmentosa GTPase A154, L155, L161, M163, W164, I172, H201, A203, F204, V205, L211, V213, F214, L222, L228, H254, V256, V257,
regulator V263, F266, L274, L280, I289, H306, A308, L309, L315, M316, F319, C343, H360, M361, V362, V363, A365
819 Ectodysplasin-A Q92838 L90, V251, L253, V262, L271, L293, V295, Y301, I303, V307, V309, Y311, I312, F314, A318, Y320, V322, I336, C346,
(Ectodermal dysplasia I360, V362, I369, I371, M373, F380, A382
protein)
820 Canalicular multispecific Q92887 A668, V669, L680, A683, M684, I1330, V1332, V1333, L1343, L1347, F1348
organic anion transporter 1
821 Tumor necrosis factor Q92956 C53, C54, C57
receptor superfamily
member 14
822 Lipoma-preferred partner Q93052 C444, L451, C476, I483, A494, F500, C524
823 Homogentisate 1,2- Q93099 L61, Y62, W97, F112, V113, L119, C120, L131, A132, I133, I135, F136, L137, C138, C146, F147, F154, L155, I156,
dioxygenase (EC 1.13.11.5) V157, L163, I165, F169, M172, V174, I179, C180, V181, I182, M186, F188, I190, Y199, I200, L201, V203, F208, L221,
F227, V239, V245, I246, L253, A256, F263, V265, A267, W268, Y277, V300, L301, A303, A313, F315, I317, F342,
L345, A397, F398, F400, Y423
824 Interleukin-22 receptor Q969J5 F41, L45, F61, V62, C118, L120, Y131, V135, F152, V176, L178, L183, V205, A241, I243
subunit alpha-2
825 SH3 domain-containing Q96B97 A4, V6, L18, I20, I26, W37, F48, V53, C103, V105, L117, L119, I125, V127, L140, F147, I152, C272, V274, L286, I288,
kinase-binding protein 1 V294, W307, F318, V323
826 Interleukin-17 receptor A Q96F46 L48, V93, A94, I96, W98, A112, L114, F129, L135, F144, F149, V150, V151, Y157, V159, V161, H163, V182, M190,
C196, L217, V219, F221, Y230, I232, L234, V281, I283, F287
827 Leucine-rich repeat and Q96FE5 V55, C57, L76, L78, I83, L86, F91, L97, L100, L102, V107, A114, F115, L118, L121, L124, L131, V138, L142, L145,
immunoglobulin-like L148, I150, L158, F163, L166, L169, L172, V174, L179, A186, F187, L190, L193, L196, L198, C201, A210, L211, L214,
domain-containing nogo L217, L220, L222, I230, L241, L244, I246, W249, L252, C259, L260, L265, L268, I270, A282, L286, L289, I299, L310,
receptor-interacting protein L313, L318, L323, A330, F331, L334, L340, V342, L347, L350, V354, L361, L364, L366, L371, L377, V380, F381,
1 L387, F389, C396, V402, F407, A424, F444, C446, W458, L482, V484, A487, Y495, C497, A499, A510, L512
828 PDZ and LIM domain Q96HC4 L8, W14, L28, I30, A39, V49, V50, I53, A58, M61, A66, I70, L77, M79, L81, C420, I427, L432, C446, M453, F458,
protein 5 V459, C467
829 E3 ubiquitin-protein ligase Q96J02 L20, I22, V24, V43, V45, V47, V71, V73, L79, F81, V83, L95, I102, L106, L113, L122, L135, I137, L139, L328, L440,
Itchy homolog F456, F496, F535, C539, I550, V552, F558, I565, L573, V579, I580, V592, W596, F597, L600, L611, F638, F640, I641,
F644, I645, A646, M647, A648, Y664, I667, L677, F705, A742, F757, F761, I764, L765, L770, F773, L778, L782, W793,
I809, F812, F815, V816, M825, L827, L828, V831, F842, F854, C855, I856, C871, L875, L877, L886, L890, A893, I894
830 Serine/threonine-protein Q96J92 L210
kinase WNK4 (EC 2.7.11.1)
831 Roundabout homolog 3 Q96MS0 C143, I572, L574, I591, V616, F627, V629, A631
832 NACHT, LRR and PYD Q96P20 L10, L14, F25, L29, L54, A55, M58, A67, W68, A69, M70, A71, I74, F75, A87
domains-containing protein
3
833 Interleukin-17F Q96PD4 C102, C107, V129
834 SLIT and NTRK-like protein Q96PX8 Y61, L63, L65, L70, L73, F78, L87, M89, L94, A101, F102, L105, V108, L111, I113, I118, F121, L129, L132, L135,
1 A137, L142, A149, F150, L153, L156, L159, L161, I166, V173, F174, L182, L184, L189, V197, L198, I201, I207, L208,
L209, W214, C216, L220, L223, A234, V239, C241, L247, L252, I387, I390, F395, L401, L404, L406, I411, F419, L422,
L425, L428, M430, L435, L438, F443, L446, L449, L452, V454, I459, I462, F467, M470, L473, L476, L478, L483, V490,
F491, L496, L499, L501, F506, V514, L515, I524, L526, W531, I537, F540, L556, F569
835 Membrane-associated Q96QZ7 F318, Y377, L475, L496, I498, A507, M513, V518, I519, V520, V522, V527, L528, V535, V548, L550, L552, C553,
guanylate kinase, WW and I646, I686, V689, V694, V702, V715, L717, V719, I842, L844, I865, I867, A876, L888, I889, V891, V896, V904, A911,
PDZ domain-containing V917, L919, V921, V999, I1001, I1038, A1047, L1053, V1062, I1075, V1086, L1088, V1153, L1166, L1176, A1187,
protein 1 M1193, I1199, I1202, A1215, L1218, V1226, L1228, L1230
836 Envelope glycoprotein Q993A8 A13, M38, V44, M47, I51, V63, V70, I97, L136, A167, I168, C182, V185, I194, L202, L203, V213, I227, I228, V229,
gp160 L231, V235, I237, C239, M269, C274, I276, W281, L285, I288, A289, L292, I302, I303, F304, H317, F319, C321, F326,
C328, L333, F334, L359, C361, I366, I367, V373, A376, M377, I392, L395, L396, L397, I410, F411, M418, W422, L426,
V432, I434, V448, I491, V492, L498, L499, A501, I502, A504, L508, L509, V513, I516, L519, I523, I578, I585
837 Neurogenic locus notch Q99466 C472, C510, C548, C586, C965, L1638, H1639, A1641, A1642, A1650, L1671, H1672, A1674, V1675, A1679, V1682,
homolog protein 4 C1683, L1686, L1705, M1706, L1707, A1708, A1709, L1716, L1720, A1737, L1738, H1739, A1741, A1742, A1749,
A1750, L1753, L1771, F1772, L1773, A1774, A1775, V1782, A1783, L1786, V1806, A1807, L1815
838 Protein deglycase DJ-1 Q99497 A6, L7, V8, I9, L10, A11, A14, V25, M26, V33, A36, L58, A61, Y67, V69, V70, V71, L72, A79, L82, V88, L92, I102,
A103, A104, I105, A111, L112, L113, H115, I117, V123, M133, M134, I152, L153, F164, A165, I168, V169
839 Histone H2B type 1-N Q99877 V42, V45, L46, A59, M63, V67, I70, F71, I74, A75, A78, A82, I90, I95, A98, V99, L103, A108, A111, A118
840 Myocilin (Myocilin 55 kDa Q99972 V269, W270, W286, I288, V298, Y301, F307, H316, L318, A327, V329, L334, F336, V344, I345, Y347, L349, I360,
subunit) (Trabecular A363, L381, V383, L388, V390, I391, I401, L403, L406, L411, V426, A429, F430, I431, I432, L436, V449, M476,
meshwork-induced L486, W489, M494
glucocorticoid response
protein) [Cleaved into:
Myocilin, N-terminal
fragment (Myocilin 20 kDa
N-terminal fragment);
Myocilin, C-terminal
fragment (Myocilin 35 kDa
N-terminal fragment)]
841 Semaphorin-3C Q99985 L305, L449, L472, I473, I491, L526
842 Sclerostin Q9BQB4 C80, L146, C165
843 Programmed cell death Q9BUL8 L22, A41, A46, A51, L81, F100, L103, A107, L110, L114, I117, F127, I134, L141, V145, V148, L160, F167, F174,
protein 10 V190, F191, A194, L197, I198, I204, L205, F208
844 Brother of CDO Q9BWV1 V622, V624, W626, F639, V641, I668, Y677, F679, V681, A683, V701, I718, I729, L731, F748, I750, I777, Y786, I788,
M790, C792
845 Complement C1q tumor Q9BXJ0 A108, L123, F125, F143, C145, Y151, F153, V155, V159, L164, L168, L199, V205, V207, F227
necrosis factor-related
protein 5
846 Periaxin Q9BXM0 V44, A53
847 Complement factor H- Q9BXR6 Y53, I70, C87, V110, I127, C129
related protein 5
848 Disintegrin and Q9BZ11 L212, L214, Y215, I216, V217, A218, L237, V240, V244, L247, L248, I253, W263, L279, F282, L283, A298, L300,
metalloproteinase domain- L301, V328, A339, A340, M343, A344, I347, L351, M373, L405, C433, C444, C457, C462, C488, C495
containing protein 33
849 NACHT, LRR and PYD Q9C000 L13, L21, F24, L28, V53, A54, L57, A66, A70, W74, L82, V136, F365, F801, A824, V825, L828, L842, L844, C847, L849,
domains-containing protein C854, L870, L872, L877, A882, C886, L899, C904, C910, C911, L918, L927, L929, V939, L942, C943, L946, L953,
1 L956, L958, M967, L971, L974, I983, L1379, V1382, L1389, I1390, V1393, V1396, V1399, L1400, L1403, L1408,
V1416, M1426, L1429, L1444, A1447, L1448, L1459
850 MCG4778 Q9D1H1 L75, F77, I79, L82, I88, I103, L107, L110, V140, C144, A150, I158, F162, L172, V182
851 Amyloid beta A4 precursor Q9DBR4 V594, L611, A614, V630, M632, V639, V641, C654, V656, L659, F661, M662, V664, F671, A672, F673, I674, C684,
protein-binding family B V686, F687, C689, A693, V696, V700, A703, N738
member 2
852 Sperm-egg fusion protein Q9EQF4 M28, C47, W50, C55, C86, A93, C95, F96, C99, L103, V120, V123, L125, C126, C130, W133, C137, F169, F173, L179,
Juno C180, I183, F188, C200, L201, V216
853 Fibroblast growth factor 23 Q9GZV9 H41, L42, L53, I55, A72, L73, I85, L94, C95, M96, C113, F115, V126, L135, V136, F157
854 ADP-ribosylation factor-like Q9H0F7 V20, L21, C22, L23, I33, I34, F58, M70, A89, I90, F92, V93, I94, V104, L109, L112, I118, I125, L126, F127, F128,
protein 6 A129, V143, L149, C160
855 Magnesium transporter Q9H0U3 L44, I54, M56, L64, V65, Y72, V74, I75, V76, M77, F78, C90, A93, F97, L100, A101, I114, F116, V119, V127, F128,
protein 1 F139, A163, I166, I170
856 ATP-binding cassette sub- Q9H221 L195, L234, L264, A422, A546, A548, A549
family G member 8
857 ATP-binding cassette sub- Q9H222 V72, I81, M82, C83, I84, L85, L95, L96, L139, L142, V144, L148, Y150, A155, V168, M172, I185, A204, M214, L215,
family G member 5 F216, L235, A239, I244, V245, I249, I263, A264, F273, M280, F284, F298, Y301, Y329, L371, V375, A415, L423,
F426, V427, M435, A438, F442, V448, Y458, M463, M464, A466, Y467, V471, A478, F482, C486, Y487, L490, L492,
A505, L506, A508, H510, L511, L518, L521, V530, V534, C571, I574, L575, V576, F580, C613, A616, L627, F642
858 Cadherin-23 Q9H251 I42, L55, F78, V87, L89, V103, F105, V107, V118, I120, V122, V154, V187, V189, V205, A207, L222, I224
859 DnaJ homolog subfamily C Q9H3Z4 L16, Y17, L20, I31, A53, I60, A63, L67, I75, V95
member 5
860 SPARC-related modular Q9H4F8 I416
calcium-binding protein 1
861 Anthrax toxin receptor 1 Q9H6X2 L45, Y46, F47, I48, L49, V55, I62, Y63, F65, V66, L69, L78, M80, F82, I83, V84, F85, L109, L113, M120, F124, A127,
I131, I145, I146, A147, L148, F159, A165, V175, C177, V178, V180, L188, I191, A192, L208
862 Pleckstrin homology Q9HB21 L14, F30, L32, F39, F81, V82, M83, L92, W103, V106, L107, C198, L215, I220, I235, C246, L257, F258, I260, V269,
domain-containing family A V284
member 1
863 Transient receptor potential Q9HBA0 L487
cation channel subfamily V
member 4
864 Interleukin-21 Q9HBE4 L35, V39, L42, A56, C64, A68, F69, C71, F72, L77, I89, L96, F129, L130, F133, L136, L137, I141
865 E3 ubiquitin-protein ligase Q9HCE7 I15, L17, V19, A22, L25, L33, A38, I40, V42, L68, I76, I78, V80, I86, F94, I133, V135, F324
SMURF1
866 Roundabout homolog 2 Q9HCK4 C110, A435, L437, W451, L473, L478, Y486, C488, A490, A501, L503, V538, L540, I557, V582, F593, V595, A597,
V637, V652, V654, I665, Y668, V670, L699, I710, V712
867 Golgi-associated PDZ and Q9HD26 L291, I313, I315, A324, L330, A335, I336, A338, V339, L344, A352, L356, I363, F365, V367
coiled-coil motif-containing
protein
868 Neurexin-3-beta Q9HDB5 I96, L113, V115, F117, I125, L126, V127, I129, L139, L141, I143, I148, V150, F152, I159, I161, V168, V176, A185,
L187, V189, V194, L204, F207, I213, I215, F224, L228, L231, Y233, V238, L239, V255, V261
869 Neuraminidase (EC Q9IGQ6 L85, I106, V114, V116, F121, I122, F132, F133, L134, L158, C161, A178, W179, A181, A183, C184, L191, I193, I195,
3.2.1.18)/strain A/Brevig A202, V203, A204, L206, L224, A232, C233, V234, F239, I241, M242, A251, Y253, I255, I258, V263, H275, Y276, C279,
Mission/1/1918 H1N1 C281, Y282, V288, C290, V291, C292, V304, F306, L310, C318, V321, F322, F349, F351, Y353, V357, W358, I359,
(Influenza A virus (strain F371, M373, I374, F387, I393, V394, F406, V407, M418, C421, F422, W423, V424, L426, W437, I443, F445
A/South Carolina/1/1918
H1N1))
870 Spike glycoprotein Q9J3E7 L79, V87, F92, F100, I104, A106, V108, F123, I126, V127, I128, F132, V139, V140, I141, I148, V152, C153, C158,
C165, A201, F202, F206, F213, A215, F226, I232, V241, L242, F244, C246, Y258, V260, A482, Y891, V900, V906,
A994, A1053, L1067, I1113
871 Interleukin-23 subunit alpha Q9NPF7 C33, L40, A44, L82, C89, L90, I93, H94, L97, Y100, F109, L124, L128, L131, L150, L169, V173, A176, V179, F180
872 SLAM family member 7 Q9NQ25 F39, I51, W53, L90, L95, L122, V124, Y125, L128, W164, L180, C195
873 Serine protease inhibitor Q9NQ38 C30, F33, C44, C63, C66, C161, L173, C194, C197, C225, L237, C258, C261, C297, L309, C330, C333, C367, L379,
Kazal-type 5 C400, C403, C437, L449, C470, C473, C496, L508, C529, C532, C567, L579, C600, M602, C603, C632, L644, V653,
C665, M667, C668, C707, L719, C740, C743, C774, L786, C807, C810, C849, L861, C882, C885, C916, L928, C949,
C952, C1014, Y1021, L1027, C1028, I1040
874 Ubiquitin carboxyl-terminal Q9NQC7 V131, V133, V146, V165, L167, C193, V195, F196, V236, L238, V249, L255, V265, V267, C286, I295, A476, I488,
hydrolase CYLD (EC A502, L504, A531, I594, L603, L607, F608, C609, L610, F611, A612, Y633, L640, V645, V654, I659, L662, L666, F685,
3.4.19.12) L689, I693, L700, I717, I730, F745, L752, I754, M756, L775, I777, L780, C788, C802, F816, A863, V864, L865, C866,
A874, F875, V876, L886, F888, V906, C909, V912, A935, C945, Y947
875 Potassium voltage-gated Q9NS40 I30, A32, C44, F48, C49, M51, V59, C64, C66, I82, A83, V96, Y98, I112, I127, A766, A781, L785, I790, I807, F808,
channel subfamily H V825, A827, L833, V844
member 7
876 Septin-11 Q9NVA2 F42, I44, L45, C46, V47, L57, M58, V92, L94, L96, V99, Y114, I117, I121, F125, L129, A149, C150, L151, I154, M169,
L172, V176, I178, I179, I181, I182, A183, F196, I200, M228, F234, V237, A252, V262, F270, L273, M276, L285,
H293, Y294
877 Alpha-parvin Q9NVD7 L268, V272, H275, L276, V283, L286, F290, L296, V297, L299, M300, V308, V327, A330, M334, L339, I349, L358,
V360, L361, L364
878 Sodium channel subunit Q9NY72 L43, C45, V60, W62, V103, I105, V107, Y118, C120, V122
beta-3
879 Endoplasmic reticulum Q9NZ08 F47, Y57, Y63, L65, I67, L71, F76, V82, I84, A86, I93, I94, L95, A105, L107, L115, L123, I131, A132, L133, L139, L140,
aminopeptidase 1 (EC V141, Y145, V147, V148, I149, Y151, Y163, L177, A178, F182, A186, A187, A190, F191, C193, F194, A201, F203, I205,
3.4.11.—) I207, F236, M242, Y245, L246, V247, A248, F249, I250, I251, V267, V269, A271, A279, Y281, A282, L283, A285,
A286, L289, L290, Y293, F297, L308, A309, A310, I311, F314, A318, M319, W322, L324, Y327, A331, L332, L333,
I347, V351, A352, L355, A356, H357, W359, F360, L363, M366, W369, L372, W373, L374, F378, A379, F381, M382,
V387, L394, V396, F405, A407, M408, A412, V419, V423, M432, V436, A442, C443, I444, L445, L448, F457, I461,
L465, L478, W479, M482, V517, M520, M521, W524, F530, L532, I533, I535, V542, M544, Y549, W563, V565, L567,
L582, F600, M604, Y607, Y608, I609, V610, L620, L624, V631, A637, L639, I640, A643, L646, I654, A657, L658,
L660, Y663, L664, V673, L680, M687, V695, F699, F702, L703, L731, L732, A735, C743, A747, V767, A770, V771,
A776, W782, L785, I801, A804, L805, C806, L814, L817, L818, I827, F832, I835, L836, I839, A849, W850, L853,
L860, F864, I871, M874, V875, F882, V891, F895, L898, L905, I915, I929, L933
880 Interleukin-1 receptor Q9NZN1 L66, V347
accessory protein-like 1
881 Programmed cell death 1 Q9NZQ7 V21, M36, I38, C40, L53, V55, W57, M59, I64, I65, F67, Y81, L92, A97, A98, L99, I101, V104, Y112, C114, I116, I126,
ligand 1 V128, A132, Y134, L153, C155, A157, A163, W167, V193, L197, F207, C209, F211, L214, L224, I226
882 Potassium voltage-gated Q9NZV8 L66, F84
channel subfamily D
member 2
883 Signal-regulatory protein Q9P1W8 A49, L51, C53, V64, W66, I104, I109, C119, V120, F166, C168, F173, W182, A211, V213, L215, V224, C226, V228,
gamma L244, A247, I248, V269, C271, V273, F276, L283, W285, C329, V331
884 Spastin (EC 3.6.4.3) Q9UBP0 V116, A123, A130, A145
885 Glyoxylate Q9UBQ7 V9, V11, L23, A24, A26, V49, A50, A52, L55, L56, C57, V63, L68, V77, I78, I93, A112, A115, L118, L119, C123, V156,
reductase/hydroxypyruvate I158, A167, I168, A169, L172, L181, A192, L205, A206, F211, I212, V213, V214, C226, F230, F231, A238, V239,
reductase (EC 1.1.1.79) F240, I241, V248, L254, A257, A264, A266, L268, V270, L282, A309, A310, L313
886 Beta-1,4- Q9UBV7 L95, A96, V97, L98, V99, F111, V112, M115, L119, I128, V130, L131, A142, L144, I145, V147, I159, A160, H162,
galactosyltransferase 7 L166, L167, L173, Y175, H184, V185, A186, L190, V200, I203, L204, L205, L206, Y211, M217, F231, I235, L242,
L258, A262, A305, L310, I312, C324
887 Fibulin-5 Q9UBX5 C166, C286
888 5′-AMP-activated protein Q9UGJ0 M265, C270, I273, V289, A292, L296, A304, L306, L318, I320, F323, I324, I326, L327, L341, I346, A368, L370, A373,
kinase subunit gamma-2 V374, L377, L385, V387, L399, H401, I404, L405, L408, F420, L425, I430, I445, A448, L449, I457, L460, V462, Y473,
V478, A482, L490, V494, L498, C511, L517, I520, V529, L532, V533, V534, V535, I545, L547, I550, L551, A553, L554
889 Deleted in malignant brain Q9UGM3 A1896, V1899, I1901, V1910, C1911, A1920, V1922, V1923, C1924, A1981, V1983
tumors 1 protein
890 Interleukin-20 receptor Q9UHF4 M50, L54, L82, C95, L97, A110, V112, I151, V153, M172, L179, Y181, V183, V185, V216, V218
subunit alpha
891 Doublecortin domain- Q9UHG0 I141, L143, I144, I158, V169, V173, L187, V195, Y207, V208, A209, V210, Y220
containing protein 2
892 DNA polymerase subunit Q9UHN1 L69, C73, F78, L79, L106, L110, W114, V118, V125, A130, L185, A189, L190, Y193, L197, Y206, L208, A209, C214,
gamma-2, mitochondrial A237, L239, V240, W241, F242, W255, W262, W263, F266, F273, L289, F293, W295, I303, L303, L311, L322, V335,
(EC 2.7.7.7) L336, V338, L342, M346, L347, A348, Y349, V371, L372, L374, L378, A379, V383, A384, L385, V387, L395, C399,
L402, L406, L407, L418, I437, L438, V441, V443, I453, L471
893 C-type lectin domain family Q9UHP7 C86, F87, C103, A108, L110, A111, V113, L122, H131, W132, I133, L135, F155, C163, A164, L166, I183, C184
2 member D
894 Apolipoprotein Q9UIR5 W35, C60, C71
895 Gap junction delta-2 protein Q9UKL4 C62
896 Endoplasmic reticulum Q9UKM7 V253, F257, A260, Y264, A268, L274, L287, L289, L291, I292, A294, L295, M298, A310, V314, L318, F320, V326,
mannosyl-oligosaccharide L328, I335, L336, L339, L340, A342, F351, A355, F358, L362, A365, I372, V377, I379, V395, I401, L403, F405, L408,
1,2-alpha-mannosidase (EC F417, V421, V424, I428, L438, V439, I443, L458, A462, Y466, Y468, L470, I474, Y487, A490, I491, V494, L498, F509,
3.2.1.113) V510, L513, M522, C527, L529, L533, A534, H545, L548, A549, L552, M553, C556, M559, L567, V572, V585, L596,
V601, L604, F605, L607, Y616, I623, L624, I641, V644, M656, F660, L661, L665, Y667, L668, L670, L671, V685, F686,
A690, H691, L693
897 Disintegrin and Q9UKQ2 C423, C434, C452, C453, C485
metalloproteinase domain-
containing protein 28
898 Frizzled-4 Q9ULV1 I50, C53, A75, L79, L94, F97, L98, C99, V101, Y102, V103, C117, C121, V124, C128, L132, F135, L143
899 Heat shock factor protein 4 Q9ULV5 L21, L24, L27, V28, I37, F46, V48, F54, V58, L59, F71, L75, F101, F106, L114, V117
900 Neurogenic locus notch Q9UM47 C194, C428, C466, C504, C617, C884, C921, C1405, C1417, F1437, C1446, C1451, F1456, C1475, A1476, L1513,
homolog protein 3 V1514, L1515, V1517, L1524, F1531, L1535, L1539, V1582, L1584, I1586, A1604, A1607, A1608, L1611, A1613
901 Unconventional myosin-VI Q9UM54 A9, I31, A43, C63, L65, A71, L73, L74, I77, I86, V90, I93, L94, I95, A96, I103, I112, V127, F128, A129, I130, A131,
A134, M138, V140, I147, I148, V149, A155, V164, Y167, L168, A185, L188, L189, A191, F192, A195, F206, F209, I212,
F214, V220, I235, Y245, H246, I247, F248, Y249, L251, C252, L265, F271, Y273, L274, Y281, F282, I318, M320,
M324, I327, L337, V340, V341, A342, V344, L345, L347, I350, L372, C375, A376, L378, L379, L381, L386, L390, A416,
A419, A422, L423, A424, V427, Y428, L431, F432, V435, V436, V439, I452, V454, L455, F471, Y475, C476, L480, F483,
F484, I488, L489, Y496, C514, I515, L517, I518, I525, I528, L529, F543, V547, F577, I578, I579, V586, Y588, F593,
L605, I609, I617, L651, L654, L655, L658, F665, I666, C668, I669, I685, L689, M694, V697, L698, M701, Y705, A709,
L714, Y718, Y721, L729, F734, C735, A737, L738, F739, L753, V756, F757, F758, F763, A764, I769, L777, L780, V784,
I1171, F1180, A1204, H1205, F1206, A1212, M1215, L1226, V1227, M1235, L1245, F1258, W1262, L1271, A1274,
I1275, A1280, A1285, L1289
902 Rho GTPase-activating Q9UNA1 A761, A763, L775, F783, V786, L795, I806
protein 26
903 Tumor necrosis factor ligand Q9UNG2 A82, F84, C100, V101, L109, I111, Y117, I119, V123, A124, V137, L139, Y140, I155, V158, L164, I170, L172, V180,
superfamily member 18 W187, I189
904 Protein unc-13 homolog A Q9UPW8 L1494, L1500
905 Neuraminidase (EC Q9W7Y7 I87, V95, V97, F102, I103, F113, F114, L115, L139, C142, A159, W160, A162, A164, C165, L172, I174, I176, A183,
3.2.1.18)/strain A/Hong V184, A185, L187, L205, A213, C214, V215, F220, V222, M223, A232, Y234, I236, I239, V244, H256, Y257, C260,
Kong/156/1997 H5N1 C262, Y263, A266, I269, C271, V272, C273, V285, F287, C299, V302, F303, F330, F332, Y334, V338, W339, I340, F352,
genotype Gs/Gd M354, I355, F368, I374, I375, F387, I388, M399, C402, F403, W404, V405, L407, W418, I424, F426
906 Hemagglutinin [Cleaved Q9WFX3 V7, I20, C21, I22, A26, V33, V36, V43, L49, L50, L58, C59, L61, L67, L69, C72, I74, A75, W77, L78, L79, C84, L87,
into: Hemagglutinin HA1 W93, Y95, I96, V97, C107, Y108, L118, L122, V125, F128, F134, A151, A152, C153, Y155, A158, L165, L166, W167,
chain; Hemagglutinin HA2 L168, Y175, L178, V190, L191, V192, L193, W194, V196, H197, H198, Y209, Y215, V216, V218, Y223, A233, M244,
chain]/strain A/Brevig Y246, Y247, L250, L251, I257, F259, A261, L265, I266, A267, Y270, A271, F272, A273, L274, I282, I283, C292,
Mission/1/1918 H1N1 C296, A302, I303, H313, I317, V324, L329, M331, A332, A349, M361, Y366, A388, I389, A440, L452, V459, L462,
(Influenza A virus (strain V466, L470, C481, H486, C488, C492, M493
A/South Carolina/1/1918
H1N1))
907 Genome polyprotein Q9WMX2 L754, V1061, L1070, A1071, C1073, V1074, V1077, C1078, W1079, V1081, A1085, I1097, L1108, V1109, L1120,
[Cleaved into: Core protein L1130, L1132, I1140, V1142, V1158, L1161, L1169, C1171, A1176, V1177, I1179, F1180, A1190, A1192, V1193,
p21/genotype 1b (isolate F1195, V1196, V1198, M1201, Y1244, V1251, V1253, L1254, A1259, A1260, M1268, I1291, Y1293, Y1296, A1301, I1312,
Con1) (HCV) I1314, C1315, C1318, I1326, L1327, I1329, V1332, A1336, A1341, L1343, V1344, V1345, L1346, A1347, I1373, F1375,
I1380, I1385, L1391, I1392, F1393, C1394, C1400, L1403, L1407, V1432, V1434, V1435, A1436, L1440, F1444,
F1448, V1451, I1452, F1470, A1481, Y1499, L1517, C1518, C1520, Y1521, A1526, Y1528, L1539, Y1542, L1555,
W1558, V1561, I1568, F1572, L1586, V1587, A1588, A1591, C1594, W1608, L1611, H1619, L1624, L1625, L1628,
I1641, I1645, M2025, C2029, I2035, C2052, F2060, I2062, C2070, Y2090, V2091, V2093, V2102, M2105, F2122,
V2128, F2147, L2160, L2440, L2449, L2450, V2456, Y2457, A2458, A2464, Y2483, V2486, M2490, A2492, A2494,
V2497, A2499, A2507, C2508, Y2522, A2524, V2527, A2534, I2538, L2545, L2546, I2557, C2565, A2576, L2578,
V2580, L2584, V2586, V2588, C2589, A2593, L2594, V2597, V2598, L2601, A2604, V2605, Y2610, V2620, L2623,
A2626, M2634, F2636, Y2638, V2647, I2652, I2658, Y2659, C2661, C2662, A2665, A2668, A2671, I2672, L2675,
L2679, Y2680, L2685, C2693, C2698, A2700, V2703, L2704, C2708, L2712, C2714, A2718, A2719, A2720, A2721,
C2722, A2725, L2727, M2732, L2733, V2734, L2739, V2740, V2741, I2742, C2743, A2753, L2755, F2758, A2761,
M2762, Y2765, A2767, I2782, V2789, A2792, Y2801, L2803, L2811, A2812, A2814, A2815, L2828, I2831, I2832,
A2835, L2838, W2839, A2840, I2843, L2844, M2845, H2847, F2848, F2849, L2858, A2861, C2864, I2866, A2869,
C2870, Y2871, I2873, L2876, L2878, I2881, I2882, L2885, A2890, F2891, V2904, A2905, C2907, L2908, L2911,
V2913, V2918, W2919, A2923, V2926, L2930, L2931, A2937, A2938, C2940, L2944, F2945, A2948, A2960, A2961,
F2970, A2972, Y2974, I2979
908 Tumor necrosis factor ligand Q9Y275 L112, C146, L147, L149, V166, A177, L178, I185, V187, F193, F194, I195, Y196, V199, Y201, M208, H210, I212,
superfamily member 13B L224, L226, M236, C245, A248, L253, L259, L261, A262, I263, A268, V276, F278, F279, A281, L282
909 Cofilin-2 Q9Y281 V11, V14, M18, A35, V36, L37, F38, I47, I48, I55, V57, Y68, F71, V72, L75, C80, Y82, A83, L84, Y85, A87, V100,
F101, W104, A109, Y117, I124, F128, V137, L149, L161
910 Ragulator complex protein Q9Y2Q5 L11, L23, L24, L25, A42, A46, V81, A82, I83, L89, L90, L91, C92, M93, L104, A108
LAMTOR2
911 Kinesin-like protein KIF3A Q9Y496 V15, V17, V18, V19, I46, V48, V76, I85, V88, I96, A98, M110, I122, F127, I130, Y149, L150, I152, V157, L160, M195,
H216, F224, I226, I235, L246, L248, V249, A252, L267, V283, I284, L302, L310, M318, C319, A320, I322, A325, L336,
A339, A342, I345
912 Neurexin-3 Q9Y4C0 F337, L576, L582, L585, F711, I824, F875, F896, L909, L949, L988, Y993, V1022, I1101, L1118, V1120, F1122,
I1130, L1131, V1132, I1134, L1144, L1146, I1148, I1153, V1155, F1157, I1164, I1166, V1173, V1181, A1190,
L1192, V1194, V1199, L1209, F1212, I1218, I1220, F1229, L1233, L1236, Y1238, V1243, L1244, V1260, V1266
913 Dystrobrevin alpha Q9Y4J8 C258, L266, C270
914 Kallikrein-4 (EC 3.4.21.—) Q9Y5K2 I31, A46, A47, L48, V59, L60, V66, L67, A69, C72, I79, L81, L83, A99, A114, L117, M118, L119, I132, I135, C148,
V150, W153, V168, C178, C192, A193, L211, C213, L217, L220, V236, Y237, L240
915 CD2-associated protein Q9Y5K6 Y4, V6, L18, I20, I26, L38, F49, V54, C113, V115, L127, L129, I135, F157, V162, C274, L288, F290, I296, F320, A325
916 Brefeldin A-inhibited Q9Y6D5 F654, A679, Y711, F722, A739, A769, I776, I822
guanine nucleotide-exchange
protein 2
917 Cadherin-10 Q9Y6N8 L63, F102, I111, A113, I117, L127, A131, V147, I148, I150, V169, V182, I217, I218, V235, I237, A239, V255, I257,
A293, F317, L346, V348, A350, V371, I373
918 Tumor necrosis factor Q9Y6Q6 C47, C50, A113, C114, C133
receptor superfamily
member 11A
Example 4: Assays Measuring Alterations in Conformational Dynamics Alterations in conformational dynamics can be measured by standard methods known in the art. In preferred embodiments, alterations in conformational dynamics can be shown by measuring changes in melting temperatures, in urea-induced equilibrium unfolding studies, and/or Gibbs free energy as compared to the starting protein.
Changes in melting temperature can be shown by the following protocol. For example, a peptidogenic protein (0.20 mg/ml) and a starting protein (as a control) is heated from 10° C. to 72° C. in a 0.1 cm quartz cuvette with a heating rate of 1 degree×min-1 controlled by a Jasco programmable Peltier element. The dichroic activity at 209 nm and the photomultiplier tube voltage (PMTV) are continuously monitored in parallel every 0.5° C. All the thermal scans are corrected for the solvent contribution at the different temperatures. Melting temperature (Tm) values are calculated by taking the first derivative of the ellipticity at 209 nm with respect to temperature. All denaturation experiments are performed in triplicate (see Lori et al., PLoS One, 5; 8(6):e64824 (2013)).
A change in urea-induced equilibrium unfolding can be shown by the following protocol. A peptidogenic protein (final concentration 40 μg/ml) and a starting protein (as a control) is incubated at 10° C. in increasing concentrations of urea (0-8 M) in 25 mM Tris/HCl, pH 7.5, in the presence of 0.2 M NaCl and 2 mM DTT (for non-disulfide containing proteins). After 10 min, equilibrium is reached and the intrinsic fluorescence emission, absorbance at 287 nm, and/or far-UV CD spectra (0.5-cm cuvette) are recorded in parallel at 10° C. To test the reversibility of the unfolding, a peptidogenic protein is unfolded at 10° C. in 7.0 M urea at 0.4 mg/ml protein concentration in 25 mM Tris/HCl, pH 7.5, in the presence of 2 mM DTT and 0.2 M NaCl. After 10 min, refolding is started by 10-fold dilution of the unfolding mixture at 10° C. into solutions of the same buffer used for unfolding containing decreasing urea concentrations. The final protein concentration is 40 μg/ml. After an incubation period of 15 min to 24 h, the intrinsic fluorescence emission, absorbance at 287 nm, and/or the CD spectra are recorded as a function of urea concentration at 10° C. (see Lori et al., PLoS One, 5; 8(6):e64824 (2013)).
Alterations in Gibbs free energy can be shown by the following protocol. In order to measure Gibbs free energy, differential scanning calorimetry (DSC) experiments are performed on a VP-DSC (Microcal Inc., Northampton, Mass.) instrument at a scan rate of 1.5 deg/minute. Where possible, temperature-induced unfolding of a peptidogenic protein is checked for reversibility by comparing first and second DSC scans. It is understood that reversibility of folding and unfolding is not a requirement for the peptidogenic proteins described herein. The partial molar heat capacity of the protein, Cp,pr(T), is obtained from the experimentally measured apparent heat capacity difference between the sample (containing protein solution) and reference (containing corresponding buffer solution) cells, ΔC_p{circumflex over ( )}app (T). Protein concentration is measured spectrophotometrically using a known molar extinction coefficient. Analysis of the heat capacity profiles according to a two-state model is done using non-linear regression routine NLREG and in-house written scripts. The standard thermodynamic functions under reference conditions are calculated as:
Where ΔH(T), ΔS(T), and ΔG(T) are the enthalpy, entropy and Gibbs energy functions of a peptidogenic protein, respectively, ΔHcal is the enthalpy of unfolding at the transition temperature Tm, and ΔCp is the heat capacity of unfolding (see Loladze et al., J. Mol. Biol. 320, 343-357 (2002)).
Example 5: Assays Measuring Peptidogenicity One of the intracellular conditions that may participate in processing of the peptidogenic proteins as described herein is proteolysis. The influence of the differential stability of the peptidogenic proteins on proteolysis can be determined using one of several in vitro or ex vivo assays.
(a) Cathepsin L Proteolysis
In one embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by subjecting them to the action of cathepsin L, one of the enzymes known to be critical in protein antigen processing (Hsieh, C. S., deRoos, P., Honey, K., Beers, C., and Rudensky, A. Y. (2002) J. Immunol. 168, 2618-2625). Susceptibility of the peptidogenic proteins to proteolysis is assessed using lysosomal cathepsin L. The peptidogenic proteins (0.5 ug/ul) are incubated with various amounts (e.g., 1.5 munits) of enzyme in 50 mM sodium acetate buffer, pH 4.5, for various lengths of time at 37° C. Digestion is stopped using 0.1% TFA, and proteolysis is monitored by reversed-phase HPLC on C18 reverse phase columns (Vydac, Hesperia, Calif.). Elution of the proteolytic products is carried out with a linear gradient of acetonitrile/water containing 0.1% TFA.
(b) Proteolysis Using Alpha-Chymotrypsin and Carboxypeptidase Y
In another embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by subjecting them to the action of alpha-chymotrypsin and carboxypeptidase Y. Alpha-chymotrypsin is an endopeptidase which cleaves at the carboxyl terminus of aromatic amino acids; carboxypeptidase Y is an exopeptidase which removes amino acids sequentially from the carboxyl terminus. Proteolytic digestion with these enzymes is specific for unstable conformations, hence, the conformational stability of the peptidogenic proteins determines their resistance/susceptibility to proteolytic digestion. The peptidogenic proteins at 1 mg/ml in 0.5 ml of 20 mM HEPES-buffered saline, pH 7.5, are incubated at 37° C. with 100 μg of alpha-chymotrypsin from bovine pancreas and carboxypeptidase Y from yeast. Each incubation is terminated at various time-points and the digested samples are stored at −20° C. until analyzed. Samples are analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), through a 15% acrylamide gel and under reducing conditions, then stained with Coomassie Brilliant Blue for visualization.
(c) Proteolysis Using Lysosomal Extracts
In another embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by subjecting them to the action of lysosomal extracts of bone marrow-derived dendritic cells. The peptidogenic proteins are incubated at various concentrations in the presence of equal amounts of proteins from crude lysosomal extracts from bone marrow-derived dendritic cells. The mixtures are incubated in 0.1 M sodium citrate buffer, 0.5% Triton X-100, and 2 mM dithiothreitol at pH 4.5. Each incubation is terminated at various time-points and the digested samples are stored at −20° C. until analyzed. Samples are analyzed by SDS-PAGE. The experiments are repeated with and without prior adsorption of peptidogenic proteins onto an adjuvant such as aluminum hydroxide. Bone marrow-derived dendritic cells are purified with use of anti-CD11c microbeads from bone marrow cultured in granulocyte macrophage-colony stimulating factor. See, for example, Delamarre et al., FIG. 4.
(d) Proteolysis after Internalization by Bone Marrow Derived Dendritic Cells
In another embodiment, examination of the behavior of the peptidogenic proteins toward proteolysis is measured by labeling them with FITC per the manufacturer's protocol, incubating bone marrow-derived dendritic cells with the FITC-proteins, and measuring the percentage of FITC+, CD11c+ cells over time. Bone marrow-derived dendritic cells are loaded with 0.5 mg/ml of the FITC-labeled peptidogenic proteins for 1 hour, are washed, and then are cultured at 37° C. for various amounts of time. FACS is then used to determine the percentage of FITC+, CD11c+ cells at each time point subtracted to the percentage of FITC+, CD11c+ cells at time 0 h. This represents the percentage of proteolysis of the peptidogenic proteins. The experiments are repeated with and without prior adsorption of FITC-labeled peptidogenic proteins onto an adjuvant such as aluminum hydroxide.
Example 6: Antibody Production and Sequencing Ig-seq of antibody repertoires may follow previously described protocols (10, 29) with minor modifications. B cells can be isolated from the serum, spleen, or other tissues of hyperimmunized rabbits. In order to reduce the complexity of the sequencing library, this population can be sorted to enrich for CD19+CD3−CD27+CD38int memory B cells or B cells that recognize the target antigen (5, 30, 31). These cells are then lysed and mRNA is isolated using standard methods, and reverse transcribed to cDNA using 5′ RACE with 3′ primers specific for the IgH or IgL constant region (9, 32). The cDNA library is then amplified with primers containing the required paired-end adapter sequences and optional barcodes to enable quantification of template and error correction by averaging multiple reads (8, 9).
Complete determination of antibody sequences requires identifying native VH-VL pairs. As each VH and VL sequence is encoded by a separate mRNA, clonal sequencing may be performed by isolating single B cells in subnanoliter volume wells (5) or microemulsion (9) prior to mRNA isolation, reverse transcription, and overlap extension or linkage PCR. As an alternative, endogenous VH-VL pairs can be identified through partial cross-linking of purified Fabs prior to LC-MS/MS. Under the appropriate conditions, this will result in a fraction of the Fab heavy and light chains forming interchain crosslinks, and the resulting peptide masses will be used to determine native pairing.
In order to identify the antibodies raised in response to a mixture of peptidogenic proteins, sequence information can be combined with data from high-resolution mass spectrometry. Protein A-purified IgGs can be digested with papain to release the two Fabs from the Fc domain. These can then be immunoaffinity purified on a custom column prepared using the peptidogenic protein immobilized on a solid support, the eluted Fabs proteolytically digested, and the peptide products subjected to mass spectrometry. The resulting peptide masses can be compared with the complete antibody sequencing data to identify the CDR sequences that recognize the antigen. Pairing of IgG VH and VL sequences can be accomplished through chemical cross-linking of the immunoaffinity purified Fabs prior to the proteolytic digest; Young et al have demonstrated the feasibility of this approach (33).
Example 7: Immunization Using a Mixture of Peptidogenic Proteins Methods of raising antibodies in mammals are well known in the art. In one example, polyclonal antiserum against peptidogenic proteins is raised by immunization of pathogen free rabbits with a total of 500 μg of a mixture of peptidogenic proteins over a period of two months. For example, the peptidogenic proteins can be dissolved in PBS and emulsified with an equal volume of Freund's adjuvant. After the final booster, the serum of the rabbits can be separated to determine the titer of the polyclonal antiserum. To obtain monoclonal antibodies, 4-6 week old Balb/c mice can be immunized with a peptidogenic protein (for example 4 times with 2 week intervals with 10-100 μg/injection dissolved in Freunds complete adjuvant for the first injection, and Freund's incomplete adjuvant for subsequent immunizations). Splenocytes are isolated and fused with a fusion cell line such as Sp2/0 myeloma cells, followed by limiting dilution. Growing clones are screened using for example an enzyme-linked immunosorbant assay (ELISA). 96 cells plates are coated with peptidogenic proteins or with a control protein. The culture supernatant is added, followed by washing and addition of a labeled anti-mouse antibody for detection. After limited dilution cloning of the peptidogenic protein-specific antibody producing hybridomas stable hybridomas are obtained. From each cell, supernatant is collected and by affinity chromatography using protein A sepharose columns monoclonal antibodies can be purified.
Example 8: Another Example of Immunization Using a Mixture of Peptidogenic Proteins In an additional animal model, groups of 5 mice (C57BL/6J; Jackson Labs) can be subcutaneously immunized with 5 μg of endotoxin-free peptidogenic proteins emulsified in alum, which is the adjuvant most commonly used in human vaccines. Three weeks later, mice are bled and the presence of peptidogenic protein-specific antibodies can be determined by titering the seras by ELISA (direct binding of antibodies in sera to wild type BPTI or APP-KI coated, directly or indirectly (via a biotinylated tag and streptavidin), on the wells). To confirm that the peptidogenic proteins have a similar conformation as the starting protein, competitive inhibition assays are performed in which titrated amounts of starting protein and peptidogenic proteins are pre-incubated with the seras prior to adding to the starting protein coated plates. This provides additional evidence, with an immunological probe, that the 3D structure of the peptidogenic proteins has not been compromised by the engineered mutations.
To determine whether the peptidogenic proteins result in better secondary antibody responses, groups of mice can be immunized as described above, and 6 weeks after the primary immunization they can be immunized a second time. One week post-secondary immunization, mice are bled and antigen-specific antibody responses are determined by ELISA as described above. Mouse dendritic cells are pulsed in vitro with the peptidogenic proteins that can generate a strong antibody response, and 24 hrs later the peptidogenic protein-derived peptides presented by WWII are isolated and their masses analysed by liquid chromatography and mass spectrometry (LC/MS). These studies require large numbers (>107) of dendritic cells which are purified from mice previously injected with a mouse tumor line expressing FLT-3L, a cytokine that drives dendritic cell development in vivo (the spleens of these mice fill up with dendritic cells; Segura et al, 2009). To allow for peak identification and the quantification of MHCII-peptides by mass spectrometry, the peptidogenic protein can be biosynthetically labeled with stable isotopes such as 13C and 15N (during production of the recombinant protein—see above) prior to feeding to the DCs (Hoedt et al 2014).
Example 9: Immunization Using Sequences Encoding a Mixture of Peptidogenic Proteins Methods of directly injecting polynucleotides into animals are well described in the art. See, for example, U.S. Pat. Nos. 5,676,954; 6,875,748; 5,661,133. Briefly, using the known degeneracy of the genetic code, polynucleotides encoding a mixture of peptidogenic proteins described herein can be synthesized using standard DNA synthesis techniques. The polynucleotide(s) can then be directly injected into the animal, such as, for example, mice. Specifically, a mixture of polynucleotides encoding the mixture of peptidogenic proteins can be injected into the quadriceps muscles of restrained awake mice (female 6-12 week old BALB/c or Nude, nu/nu, from Harlan Sprague Dawley, Indianapolis, Ind.). In one embodiment, 50 μg of a polynucleotide in 50 μl solution using a disposable sterile, plastic insulin syringe and 28G ½ needle (Becton-Dickinson, Franklin Lakes, N.J., Cat. No. 329430) fitted with a plastic collar cut from a micropipette tip can be used to inject the mice, as described in Hartikka, J., et al., Hum. Gene Ther. 7:1205-1217 (1996)).
Alternatively, 6-week old Sprague Dawley female mice (body weight 20-25 grams) can be given 5000 ppm ZnOSO4 in their drinking water beginning 24 hours prior to injection. This amount of zinc has been shown to be able to activate the metallothionein promoter. Each mouse is then injected intravenously through a tail vein puncture with a 25 gauge needle with 30 μg of polynucleotides encoding the mixture of peptidogenic proteins complexed with 150 μg liposome (Lipofection TM) in a total volume of 30 pI. In one embodiment, the polynucleotides mixture injected into the mice encodes for different peptidogenic proteins relating to the same starting protein. Alternatively, a library of peptidogenic proteins can be encoded by the mixture of polynucleotides, wherein the library relates to different starting proteins. Animal care should be maintained throughout the study and should be performed in compliance with the “Guide for the Use and Care of Laboratory Animals”, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, National Academy Press.
After the injected polynucleotide encoding the peptidogenic proteins are delivered into the cells in the animal, the peptidogenic proteins are then expressed in vivo. The peptidogenic proteins can then stimulate the production of antibodies specific to the peptidogenic proteins. These antibodies can be isolated and used as a polyclonal mixture or further isolated into single species or monoclonals. The process of the immune response and production of antibodies against foreign antigens in vivo are well known in the art. Unlike the traditional protocols of antibody generation, the platform invention described herein allows the simultaneously raising of a group of antibodies against multiple peptidogenic proteins (whether or not they rely on the same starting protein). This simultaneous production of antibodies to multiple proteins using a mixture of polynucleotides has the potential to change how antibody production is currently being performed.
Example 10: Immunization Using mRNA Encoding Peptidogenic Proteins The methods of directly injecting in vitro transcribed (IVT) mRNA into animals are also well known in the art. See, Sahin et al., Nat Rev Drug Discov. 2014 October; 13(10):759-80; Kariko et al., Mol Ther, 2008 November; 16(11):1833-40; Kariko et al., Nucleic Acid Res, 2011, November; 39(21):e142; U.S. Pat. No. 6,511,832. For example, linearized DNA plasmid templates which encode a mixture of peptidogenic proteins can be used. All mRNAs can be designed to contain 5′ and 3′ untranslated regions, the open reading frames, and long poly(A) tails, which can help determine the translational activity and stability of the mRNA molecule after its transfer into cells.
For example, mRNAs (including a poly(A) tail) encoding peptidogenic proteins can be synthesized using triphosphate-derivatives of pseudouridine and 5-methylcytidine (m5C) (TriLink) to generate a modified nucleoside containing RNA. A 5′-cap can be added to the mRNAs by supplementing the transcription reactions with 6 mmol/1 3′-O-Me-m7GpppG, a nonreversible cap analog (New England Biolabs, Beverly, Mass.) and lowering the concentration of guanosine triphosphate (3.75 mmol/1). Purification of the transcripts can be performed by Turbo DNase (Ambion, Austin, Tex.) digestion followed by LiCl precipitation and 75% ethanol wash. The concentrations of RNA reconstituted in water can be determined by measuring the optical density at 260 nm. Efficient incorporation of modified nucleotides to the transcripts can be determined by HPLC analyses. All RNA samples can be analyzed by denaturing agarose gel electrophoresis for quality assurance. Lipofectin (Invitrogen, Carlsbad, Calif.) and mRNA are then complexed in phosphate buffer in order to enhance transfection. To assemble a 50 μl complex of RNA-lipofectin, first 0.4 μl potassium phosphate buffer (0.4 mol/l, pH 6.2) containing 10 μg/μl bovine serum albumin (Sigma, St. Louis, Mo.) is added to 6.7 μl DMEM, then 0.8 μl lipofectin is mixed in and the sample is incubated for 10 minutes. In a separate tube, 0.25-3 μg of RNA is added to DMEM to a final volume of 3.3 μl. Diluted RNA is added to the lipofectin mix and incubated for 10 minutes. Finally, the RNA-lipofectin complex is further diluted by adding 38.8 μl DMEM.
The RNA encoding the peptidogenic proteins can then be injected into the mouse models described herein. In general, a composition comprising 60 μl final volume with 1 μl lipofectin and different amounts of polynucleotides encoding the peptidogenic proteins are injected into the lateral vein using a 1-ml syringe with a 27G½ needle (Becton Dickinson, San Diego, Calif.). Alternatively, the polynucleotides can be injected via intramuscular, intradermal, intranasal, subcutaneous, intravenous, intratracheal, and intrathecal deliveries. After the polynucleotides are delivered into the cells, the peptidogenic proteins are synthesized in vivo. The immune responses triggered by the peptidogenic proteins and the subsequent production of antibodies in the animals are described herein.
Example 11: Affinity Maturing Antibodies to Peptidogenic Protein Using Phage Display Once antibodies have been raised to the peptidogenic proteins by presenting and allowing the peptidogenic protein to undergo processing by an antigen presenting cell such as described in the Examples herein, the resulting antibodies can be matured using a display approach. For example, a library of phage displaying scFvs or Fabs derived from B cell mRNA encoding the target-specific antibodies can be screened in an assay to identify those phage displaying scFvs or Fabs that immunospecifically bind to a peptidogenic protein or to a starting protein. Phage displaying scFvs or Fabs that bound to immobilized peptidogenic protein or starting protein can be identified after panning on immobilized peptidogenic protein or starting protein and assessing by ELISA for binding to immobilized peptidogenic protein or starting protein. The peptidogenic protein or starting protein that is immobilized on plates for these assays can be purified from supernatants of Sf9 cells infected with a baculovirus expression construct as described in Moore et al., Science 285:260-263 or from supernatants from HEK293 cells. Each of the identified scFvs or Fabs can then be sequenced.
To determine the specificity of each of the unique scFvs or Fabs, a phage ELISA can be performed for each scFvs or Fabs against the peptidogenic protein or starting protein and control wells. Individual E. coli colonies containing a phagemid representing one of the unique scFvs or Fabs can be inoculated into 96-well plates containing 100 μl 2 TYAG medium per well. Plates are incubated at 37° C. for 4 hours, shaking. M13K07 helper phage is then added to each well to a MOI of 10 and the plates are incubated for a further 1 hour at 37° C. The plates are centrifuged in a benchtop centrifuge at 2000 rpm for 10 minutes. The supernatant is removed and cell pellets are resuspended in 100 μl 2TYAK and incubated at 30° C. overnight, shaking.
The next day, plates are centrifuged at 2000 rpm for 10 min and the 100 μl phage-containing supernatant from each well are carefully transferred into a fresh 96-well plate. Twenty μl of 6×MPBS is added to each well, and incubated at room temperature for 1 hour to pre-block the phage prior to ELISA.
Flexible 96-well plates (Falcon) are coated overnight at 4° C. with a peptidogenic protein (directly or indirectly, at 1 mg/ml) in PBS, BSA (1 g/ml) in PBS, or PBS. After coating, the solutions are removed from the wells, and the plates are blocked for 1 hour at room temperature in MPBS. The plates are washed 3 times with PBS and then 50 μl of pre-blocked phage is added to each well. The plates are incubated at room temperature for 1 hour and then washed with 3 changes of PBST followed by 3 changes of PBS. To each well, 50 μl of an anti-gene VIII-HRP conjugate (Pharmacia) at a 1 to 5000 dilution in MPBS is added and the plates are incubated at room temperature for 1 hour. Each plate is washed three times with PBST followed by three times with PBS. Then 50 μl of an HRP-labelled anti-mouse antibody (DAKO EnVision) diluted 1/50 in 3% MPBS is added and incubated for 1 hour at room temperature. Each plate is then washed three times with PBST followed by three times with PBS. Fifty μl of TMB substrate is then added to each well, and incubated at room temperature for 30 minutes or until color development. The reaction is stopped by the addition of 25 μl of 0.5 M H2SO4. The signal generated is measured by reading the absorbance at 450 nm (A450) using a microtiter plate reader (Bio-Rad 3550).
Conversion of scFvs or Fabs to IgG1 format can be performed as follows. The VH domain and the VL domains of scFvs or Fabs that we wish to convert into IgG molecules can be cloned into vectors containing the nucleotide sequences of the appropriate heavy (human IgG1, IgG2, etc.) or light chain (human kappa or human lambda) constant regions such that a complete heavy or light chain molecule could be expressed from these vectors when transfected into an appropriate host cell. Further, when cloned heavy and light chains are both expressed in one cell line (from either one or two vectors), they can assemble into a complete functional antibody molecule that is secreted into the cell culture medium. Methods for converting scFvs or Fabs into conventional antibody molecules are well known within the art.
The purification of the IgG from the fermentation broth is performed using a combination of conventional techniques commonly used for antibody production. Typically the culture harvest is clarified to remove cells and cellular debris prior to starting the purification scheme. This would normally be achieved by using either centrifugation or filtration of the harvest. Following clarification, the antibody would typically be captured and significantly purified using affinity chromatography on Protein A Sepharose. The antibody is bound to Protein A Sepharose at basic pH and, following washing of the matrix, is eluted by a reduction of the pH. Further purification of the antibody is then achieved by gel filtration. As well as removing components with different molecular weights from the antibody this step can also be used to buffer exchange into the desired final formulation buffer.
Example 12: Assays Used to Characterize Antibodies and Measure Cross-Reactivity Antibodies (whether cross-reacting or antibodies raised against the peptidogenic protein) (including scFvs or Fabs and other molecules comprising, or alternatively consisting of, antibody fragments or variants thereof) may be screened in a variety of assays, some of which are described below to identify those antibodies that bind to the peptidogenic protein and/or starting protein.
In one particular assay, antibodies (whether cross-reacting or antibodies raised against the peptidogenic protein) that bind to a biotinylated protein (whether the peptidogenic protein and/or starting protein) can be captured on streptavidin coated magnetic beads. This assay may be applied to identify antibodies (whether cross-reacting or antibodies raised against the peptidogenic protein) that neutralize and/or bind to the peptidogenic protein and/or starting protein. Additionally, antibodies may be assayed in neutralization assays described herein or otherwise known in the art. For example, where the target protein is BlyS, antibodies may be tested for their ability to inhibit the peptidogenic protein and/or starting protein from binding to IM9 cells. In this assay, labeled peptidogenic protein and/or starting protein (e.g., biotinylated) is incubated with antibodies to allow for the formation of protein-antibody complexes. Following incubation, an aliquot of the protein-antibody sample is added to IM9 cells. Binding may be determined using techniques known in the art. For example, the binding of biotinylated protein (whether the peptidogenic protein and/or starting protein) to IM9 cells may be detected using a fluorimeter following the addition of streptavidin-delfia. Biotinylated protein, if it is not bound by antibodies that neutralize the protein, will bind to the cells and can be detected. Thus, an antibody that decreases the amount of biotinylated-protein that binds to IM9 cells (relative to a control sample in which the protein had been preincubated with an irrelevant antibody or no antibody at all) is identified as one that binds to and neutralizes the protein.
Other immunoassays which can be used to analyze cross-reactivity and/or characterize the antibodies raised against the peptidogenic protein include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York.
Exemplary immunoassays are described briefly below (but are not intended by way of limitation). Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the cross-reacting antibody of interest to the cell lysate, incubating for a period of time (e.g., 1 to 4 hours) at 4° C., adding protein A and/or protein G sepharose beads to the cell lysate, incubating for about an hour or more at 4° C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody of interest to immunoprecipitate a peptidogenic protein and/or a starting protein can be assessed by, e.g., western blot analysis or mass spectrometry. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody to a peptidogenic protein and/or a starting protein and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.16.1.
Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), blocking the membrane with primary antibody (the antibody of interest) diluted in blocking buffer, washing the membrane in washing buffer, blocking the membrane with a secondary antibody (which recognizes the primary antibody, e.g., an anti-human antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g., 32P or 1211) diluted in blocking buffer, washing the membrane in wash buffer, and detecting the presence of the antigen. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected and to reduce the background noise. For further discussion regarding western blot protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.8.1.
In a further example, ELISAs comprise preparing peptidogenic protein and/or a starting protein, coating the well of a 96-well microtiter plate (directly or indirectly) with the peptidogenic protein and/or a starting protein, washing away the peptidogenic protein and/or a starting protein that did not bind the wells, adding the antibody of interest conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, washing away unbound antibodies or non-specifically bound antibodies, and detecting the presence of the antibodies specifically bound to the peptidogenic protein and/or a starting protein coating the well. In ELISAs the antibody of interest does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody of interest) conjugated to a detectable compound may be added to the well.
Further, instead of coating the well with the antigen, the antibody may be coated to the well. In this case, the detectable molecule could be the peptidogenic protein and/or a starting protein conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase). One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1. The binding affinity of an antibody to a peptidogenic protein and/or a starting protein and the off-rate of an antibody-protein interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled peptidogenic protein and/or a starting protein (e.g., 3H or 1251) with the antibody of interest in the presence of increasing amounts of unlabeled peptidogenic protein and/or a starting protein, and the detection of the antibody bound to the labeled peptidogenic protein and/or a starting protein. The affinity of the antibody of the present invention for a peptidogenic protein and/or the starting protein and the binding off-rates can be determined from the data by Scatchard plot analysis. Competition with a second antibody can also be determined using radioimmunoassays. In this case, a peptidogenic protein and/or starting protein is incubated with an antibody of interest conjugated to a labeled compound (e.g., 3H or 1251) in the presence of increasing amounts of an unlabeled second anti-peptidogenic protein antibody.
In a preferred embodiment, BIAcore kinetic analysis can be used to determine the binding on and off rates of antibodies to peptidogenic protein and/or starting protein. BIAcore kinetic analysis comprises analyzing the binding and dissociation of peptidogenic protein and/or starting protein from chips with immobilized antibodies on their surface.
Example 13: Vaccination Further, a mixture of peptidogenic proteins as described herein can be used as a vaccine. For example a concentration of 320 μg/mL in phosphate-buffered saline (PBS, 155 mM NaCl, 1 mM KH2PO4, 3 mM Na2HPO3) of the peptidogenic proteins are aseptically emulsified with an equal volume of Montanide ISA 51 to give a final vaccine concentration of 160 μg/mL. The emulsion is achieved by homogenizing the mixture in a volume of 200 mL in a 400-mL vessel at room temperature for 6 min at 6000 rpm using an Omni Mixer-ES homogenizer (Omni International, Warren-ton, VA). Each vaccine undergoes comprehensive quality control analyses to ensure general safety, purity, identity, integrity, and uniform water-in-oil droplet size. Stability of vaccines stored at 2-8° C. is evaluated regularly using mouse immunogenicity tests and physical and biochemical assays to verify the vaccine safety, potency, uniformity, purity, and integrity until 4-10 months after the termination of the human immunizations. The 160 μg/mL peptidogenic protein vaccines are diluted with the PBS/ISA 51 (the adjuvant control vaccine) to the final dose forms of 10 μg/mL or 40 μg/mL prior to immunizations. As a result of different degrees of dilution, these vaccines contained two different ratios of vaccine-containing vs. vaccine-free water droplets, namely ratios of 1:15 and 1:3 for the 10 μg/mL and 40 μg/mL formulations, respectively. The test and control vaccines may be highly viscous and require vortexing prior to and after manipulation to ensure homogeneity. The vaccine can be administered intramuscularly by needle and syringe. Vaccine-induced T-cell responses are further evaluated by means of a qualified intracellular cytokine staining assay. Peripheral-blood mononuclear cells are quantified to determine the proportion of total and memory CD4 and CD8 T cells producing interleukin-2, interferon-γ, or tumor necrosis factor (TNF).
Polynucleotides encoding a mixture of peptidogenic proteins can also be used as a vaccine by administering to a patient the polynucleotide described herein.
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