3UMH

X-ray structure of the E2 domain of the human amyloid precursor protein (APP) in complex with cadmium

Summary for 3UMH

• Entry DOI: 10.2210/pdb3umh/pdb
• Related: 3UMI 3UMK
• Descriptor: Amyloid beta A4 protein, ACETATE ION, CADMIUM ION, ... (4 entities in total)
• Functional Keywords: metal binding site, metal binding, cell surface, secretory pathway, metal binding protein
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 1
• Total formula weight: 26192.19

Authors

Dahms, S.O.,Konnig, I.,Roeser, D.,Guhrs, K.H.,Than, M.E. (deposition date: 2011-11-13, release date: 2012-01-25, Last modification date: 2024-02-28)

Primary citation

Dahms, S.O.,Konnig, I.,Roeser, D.,Guhrs, K.H.,Mayer, M.C.,Kaden, D.,Multhaup, G.,Than, M.E.
Metal Binding Dictates Conformation and Function of the Amyloid Precursor Protein (APP) E2 Domain.
J.Mol.Biol., 416:438-452, 2012

PubMed 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.

PubMed: 22245578
DOI: 10.1016/j.jmb.2011.12.057

Experimental method

X-RAY DIFFRACTION (2 Å)