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Structure of the Alzheimer's disease amyloid precursor protein copper binding domain - A regulator of neuronal copper homeostasis


Barnham, KJ; McKinstry, WJ; Multhaup, G; Galatis, D; Morton, CJ; Curtain, CC; Williamson, NA; White, AR; Hinds, MG; Norton, RS; Beyreuther, K; Masters, CL; Parker, MW; Cappai, R
2003-05-09
JOURNAL OF BIOLOGICAL CHEMISTRY
Journal Article
278
19
17401-17407
A major source of free radical production in the brain derives from copper. To prevent metal-mediated oxidative stress, cells have evolved complex metal transport systems. The Alzheimer's disease amyloid precursor protein (APP) is a major regulator of neuronal copper homeostasis. APP knockout mice have elevated copper levels in the cerebral cortex, whereas APP-overexpressing transgenic mice have reduced brain copper levels. Importantly, copper binding to APP can greatly reduce amyloid beta production in vitro. To understand this interaction at the molecular level we solved the structure of the APP copper binding domain (CuBD) and found that it contains a novel copper binding site that favors Cu(I) coordination. The surface location of this site, structural homology of CuBD to copper chaperones, and the role of APP in neuronal copper homeostasis are consistent with the CuBD acting as a neuronal metallotransporter.
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
OXIDATIVE STRESS; A-BETA; NEURODEGENERATIVE DISEASE; SUPEROXIDE-DISMUTASE; HYDROGEN-PEROXIDE; CRYSTAL-STRUCTURE; PICHIA-PASTORIS; REDUCTION; METALS; ZINC
10.1074/jbc.M300629200
Refer to copyright notice on published article.

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Creation Date 2003-05-09 12:00:00