Title of article :
Metal Binding Dictates Conformation and Function of the Amyloid Precursor Protein (APP) E2 Domain
Author/Authors :
Sven O. Dahms، نويسنده , , Ina K?nnig، نويسنده , , Dirk Roeser، نويسنده , , Karl-Heinz Gührs، نويسنده , , Magnus C. Mayer، نويسنده , , Daniela Kaden، نويسنده , , Gerd Multhaup، نويسنده , , Manuel E. Than، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2012
Abstract :
The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimerʹs 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 Alzheimerʹs disease.
Keywords :
Alzheimerיs disease , conformational change , Metal binding , crystal structure , isothermal titration calorimetry (ITC)
Journal title :
Journal of Molecular Biology
Journal title :
Journal of Molecular Biology