title: Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain.
abstract: The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimer's disease and appear essential for neuronal development and cell homeostasis in mammals. Proteolytic processing of APP is influenced by metal ions, protein ligands and its oligomerization state. However, the structural basis and functional mechanism of APP regulation are hitherto largely unknown. Here we identified a metal-dependent molecular switch located within the E2 domain of APP containing four evolutionary highly conserved histidine residues. Three X-ray structures of the metal-bound molecule were solved at 2.6-2.0 Å resolution. Using protein crystallographic and biochemical methods, we characterized this novel high-affinity binding site within the E2 domain that binds competitively to copper and zinc at physiological concentrations. Metal-specific coordination spheres induce large conformational changes and enforce distinct structural states, most likely regulating the physiological function of APP and its processing in Alzheimer's disease.
authors.affiliation: Protein Crystallography Group, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Sven O
authors.initials: SO
authors.lastname: Dahms
authors.forename: Ina
authors.initials: I
authors.lastname: Könnig
authors.forename: Dirk
authors.initials: D
authors.lastname: Roeser
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Gührs
authors.forename: Magnus C
authors.initials: MC
authors.lastname: Mayer
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaden
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Than
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D001665:Binding Sites; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D015032:Zinc / Q000737:chemistry*
chemical_list: D016564:Amyloid beta-Protein Precursor; D006639:Histidine; D003300:Copper; D015032:Zinc