Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis.
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.
Barnham
Kevin J
KJ
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
McKinstry
William J
WJ
Multhaup
Gerd
G
Galatis
Denise
D
Morton
Craig J
CJ
Curtain
Cyril C
CC
Williamson
Nicholas A
NA
White
Anthony R
AR
Hinds
Mark G
MG
Norton
Raymond S
RS
Beyreuther
Konrad
K
Masters
Colin L
CL
Parker
Michael W
MW
Cappai
Roberto
R
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
D016564:Amyloid beta-Protein Precursor; D003300:Copper