BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper.
The amyloidogenic pathway leading to the production and deposition of Abeta 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 Abeta peptides also bind copper, zinc, and iron. The first step in the generation of Abeta 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.
Angeletti
Barbara
B
Neurology & Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom.
Waldron
Kevin J
KJ
Freeman
Katie B
KB
Bawagan
Hinayana
H
Hussain
Ishrut
I
Miller
Christopher C J
CC
Lau
Kwok-Fai
KF
Tennant
Maria E
ME
Dennison
Christopher
C
Robinson
Nigel J
NJ
Dingwall
Colin
C
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D003300:Copper / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology* / Q000235:genetics; D010450:Endopeptidases; D006801:Humans; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism*
C491961:Ccs protein, rat; D018832:Molecular Chaperones; D003300:Copper; D013482:Superoxide Dismutase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human