title: Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis.
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.
authors.affiliation: Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: William J
authors.initials: WJ
authors.lastname: McKinstry
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
authors.forename: Denise
authors.initials: D
authors.lastname: Galatis
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Morton
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Williamson
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hinds
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Konrad
authors.initials: K
authors.lastname: Beyreuther
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D016564:Amyloid beta-Protein Precursor; D003300:Copper