Metal Binding Dictates Conformation and Function of the Amyloid Precursor Protein (APP) E2 Domain

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• 作者：Sven O. Dahms¹ ; Ina Kö ; nnig¹ ; Dirk Roeser¹ ; Karl-Heinz Gü ; hrs² ; Magnus C. Mayer³ ; Daniela Kaden³ ; Gerd Multhaup³ ; Manuel E. Than¹ ; ^{than@fli-leibniz.de}
• 关键词：APP ; amyloid precursor protein ; AD ; Alzheimer's disease ; CuBD ; copper binding domain ; MR ; molecular replacement ; PDB ; Protein Data Bank ; SAD ; single anomalous dispersion ; ITC ; isothermal titration calorimetry ; SPR ; surface plasmon resonance ; RU ; response
• 刊名：Journal of Molecular Biology
• 出版年：2012
• 出版时间：24 February 2012
• 年：2012
• 卷：416
• 期：3
• 页码：438-452
• 全文大小：2171 K

文摘

The amyloid precursor protein (APP) and its neurotoxic cleavage product A¦Â 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?? 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.