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BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper

Lookup NU author(s): Dr Kevin WaldronORCiD, Iftikhar Hussain, Professor Christopher Dennison, Professor Nigel Robinson, Professor Colin Dingwall


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The amyloidogenic pathway leading to the production and deposition of Aβ peptides, major constituents of Alzheimer disease senile plaques, is linked to neuronal metal homeostasis. The amyloid precursor protein binds copper and zinc in its extracellular domain, and the Aβ peptides also bind copper, zinc, and iron. The first step in the generation of Aβ is cleavage of amyloid precursor protein by the aspartic protease BACE1. Here we show that BACE1 interacts with CCS (the copper chaperone for superoxide dismutase-1 (SOD1)) through domain I and the proteins co-immunoprecipitate from rat brain extracts. We have also been able to visualize the co-transport of membranous BACE1 and soluble CCS through axons. BACE1 expression reduces the activity of SOD1 in cells consistent with direct competition for available CCS as overexpression of CCS restores SOD1 activity. Finally, we demonstrate that the twenty-four residue C-terminal domain of BACE1 binds a single Cu(I) atom with high affinity through cysteine residues. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Publication metadata

Author(s): Angeletti B, Waldron KJ, Freeman KB, Bawagan H, Hussain I, Miller CCJ, Lau K-F, Tennan ME, Dennison C, Robinson NJ, Dingwall C

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2005

Volume: 280

Issue: 18

Pages: 17930-17937

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.


DOI: 10.1074/jbc.M412034200

PubMed id: 15722349


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