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Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis.
J Biol Chem. 2003 May 09; 278(19):17401-7.JB

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+Show Affiliations

Department of Pathology, The University of Melbourne, Victoria 3010, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12611883

Citation

Barnham, Kevin J., et al. "Structure of the Alzheimer's Disease Amyloid Precursor Protein Copper Binding Domain. a Regulator of Neuronal Copper Homeostasis." The Journal of Biological Chemistry, vol. 278, no. 19, 2003, pp. 17401-7.
Barnham KJ, McKinstry WJ, Multhaup G, et al. Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. J Biol Chem. 2003;278(19):17401-7.
Barnham, K. J., McKinstry, W. J., Multhaup, G., Galatis, D., Morton, C. J., Curtain, C. C., Williamson, N. A., White, A. R., Hinds, M. G., Norton, R. S., Beyreuther, K., Masters, C. L., Parker, M. W., & Cappai, R. (2003). Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. The Journal of Biological Chemistry, 278(19), 17401-7.
Barnham KJ, et al. Structure of the Alzheimer's Disease Amyloid Precursor Protein Copper Binding Domain. a Regulator of Neuronal Copper Homeostasis. J Biol Chem. 2003 May 9;278(19):17401-7. PubMed PMID: 12611883.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis. AU - Barnham,Kevin J, AU - McKinstry,William J, AU - Multhaup,Gerd, AU - Galatis,Denise, AU - Morton,Craig J, AU - Curtain,Cyril C, AU - Williamson,Nicholas A, AU - White,Anthony R, AU - Hinds,Mark G, AU - Norton,Raymond S, AU - Beyreuther,Konrad, AU - Masters,Colin L, AU - Parker,Michael W, AU - Cappai,Roberto, Y1 - 2003/02/28/ PY - 2003/3/4/pubmed PY - 2003/7/2/medline PY - 2003/3/4/entrez SP - 17401 EP - 7 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 19 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12611883/Structure_of_the_Alzheimer's_disease_amyloid_precursor_protein_copper_binding_domain__A_regulator_of_neuronal_copper_homeostasis_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=12611883 DB - PRIME DP - Unbound Medicine ER -