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

JOURNAL OF MOLECULAR BIOLOGY

卷:416

Article

Dahms, Sven O.¹  Koennig, Ina¹  Roeser, Dirk¹  Guehrs, Karl-Heinz²  Mayer, Magnus C.³  Kaden, Daniela³  Multhaup, Gerd³  Than, Manuel E.¹ 

[1] FLI, Leibniz Inst Age Res, Prot Crystallog Grp, D-07745 Jena, Germany

[2] FLI, Leibniz Inst Age Res, Prot Lab, D-07745 Jena, Germany

[3] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany

关键词: Alzheimer's disease;    conformational change;    crystal structure;    isothermal titration calorimetry (ITC);    metal binding;   

DOI  :  10.1016/j.jmb.2011.12.057

来源: Elsevier

【 摘 要 】

The amyloid precursor protein (APP) and its neurotoxic cleavage product A beta 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 angstrom 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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free