Abstract: Provided herein is a fusion protein comprising: (a) an extracellular domain comprising a first binding moiety that is capable of specifically binding to a first cell surface marker: (b) a transmembrane domain: and (c) an intracellular domain comprising: i. a first dimerization domain that specifically binds to a corresponding target dimerization domain in a target protein: and ii. a degradation domain, wherein the degradation domain is a degron or E3 ligase-recruiting domain. Protein circuits. cells and methods that make use of the fusion protein are also provided.

Abstract: Provided herein are a variety of molecular feed-forward circuits. In some embodiments a molecular feed-forward circuit may comprise a first nucleic acid comprising a first nucleotide sequence encoding a regulatory protein that is activated by a first exogenous stimulus, and a second nucleic acid comprising a second nucleotide sequence encoding a signaling protein that is activated by the first exogenous stimulus, where the target protein has a regulatory motif and the activated regulatory protein inactivates the target protein via the regulatory motif. The molecular circuit can further comprise a controller protein that is activated by a second exogenous signal, wherein the controller protein controls the interaction between the regulatory protein and the target protein. In this circuit activation of the regulatory protein is delayed relative to the activation of the target protein. The system can be used to produce a pulse of signaling and/or a concentration filter, for example.

Abstract: Provided are molecular feedback circuits as well as nucleic acids encoding such molecular feedback circuits and cells genetically modified with the subject molecular feedback circuits. Methods of modulating signaling of a signaling pathway of a cell using molecular feedback circuits and methods of treating a subject for a condition by administering a cell containing a nucleic acid that encodes a molecular feedback circuit are also provided. Aspects of the molecular feedback circuits of the present disclosure include a signaling protein, of a signaling pathway, that includes a latent deactivation domain. Such circuits may include a regulatory sequence that is responsive to an output of the signaling pathway and is operably linked to a nucleic acid encoding a switch polypeptide that, when expressed, triggers the deactivation domain to deactivate the signaling molecule.

Abstract: Provided are molecular feedback circuits employing caged-degrons. Aspects of such circuits include the use of a caged-degron to modulate the output of a signaling pathway in a feedback-controlled manner. Also provided are nucleic acids encoding molecular circuits and cells containing such nucleic acids. Methods of using caged-degron-based molecular feedback circuits are also provided, including e.g., methods of modulating a signaling pathway of a cell that include genetically modifying the cell with a caged-degron-based molecular feedback circuit.

Abstract: Disclosed herein are non-naturally occurring cage polypeptides, kits and degron LOCKRs including the cage polypep-tides, and uses thereof, wherein the cage polypeptides include (a) a helical bundle, comprising between 2 and 7 alpha-helices, wherein the helical bundle includes: (i) a structural region; and (ii) a latch region, wherein the latch region composes a degron located within the latch region, wherein the structural region interacts with the latch region to prevent activity of the degron; and (b) amino acid linkers connecting each alpha helix