Abstract: Members of the Amyloid Precursor Protein family (APP molecules) and their neurotoxic cleavage product A? are key players in the development of Alzheimer's disease (AD). Proteolytic processing of APP molecules is influenced by metal ions, protein ligands and its oligomerization state. X-ray structures of the metal bound molecule at 2.6-2.0 ? resolution are presented, providing structural and functional bases for the regulation of APP molecules using conformational information. A metal-dependent molecular switch located within the E2 domain of APP coinciding with a high affinity copper and zinc binding site within the monomeric E2 domain was evaluated. The metal specific coordination spheres of this E2 domain comprise four evolutionary conserved histidine residues. Metal binding induces large conformational changes relative to the metal free protein. This conformational change provides a basis for influencing APP molecule processing and thus trafficking and the production of A?.