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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.

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  • Publisher Full Text

    • Authors+Show Affiliations

    Barnham KJ
    Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
    McKinstry WJ
    No affiliation info available
    Multhaup G
    No affiliation info available
    Galatis D
    No affiliation info available
    Morton CJ
    No affiliation info available
    Curtain CC
    No affiliation info available
    Williamson NA
    No affiliation info available
    White AR
    No affiliation info available
    Hinds MG
    No affiliation info available
    Norton RS
    No affiliation info available
    Beyreuther K
    No affiliation info available
    Masters CL
    No affiliation info available
    Parker MW
    No affiliation info available
    Cappai R
    No affiliation info available

    MeSH

    Alzheimer DiseaseAmino Acid SequenceAmyloid beta-Protein PrecursorBinding SitesBiological TransportCopperHumansMolecular Sequence DataNeuronsProtein BindingProtein Conformation

    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 -