Structure of the Alzheimer's disease amyloid precursor protein copper binding domain - A regulator of neuronal copper homeostasis
Details
Publication Year 2003-05-09, Volume 278, Issue #19, Page 17401-17407
Journal Title
JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type
Journal Article
Abstract
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.
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords
OXIDATIVE STRESS; A-BETA; NEURODEGENERATIVE DISEASE; SUPEROXIDE-DISMUTASE; HYDROGEN-PEROXIDE; CRYSTAL-STRUCTURE; PICHIA-PASTORIS; REDUCTION; METALS; ZINC
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2003-05-09 12:00:00
Last Modified: 0001-01-01 12:00:00
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