BACE1 Cytoplasmic Domain Interacts with the Copper Chaperone for Superoxide Dismutase-1 and Binds Copper

• DOI: 10.1074/jbc.m412034200
• Publication Date: 2005-02-19T01:12:44Z
• Authors: Barbara Angeletti; Kevin J. Waldron; Katie B. Freeman; Hinayana Bawagan; Ishrut Hussain; Christopher C.J. ...; Kwok-Fai Lau; Maria E. Tennant; Christopher Dennison; Nigel J. Robinson; Colin Dingwall
• Keywords: Cytoplasm; 0303 health sciences; Binding Sites; Superoxide Dismutase; 610; Protein Structure, Tertiary; Rats; 03 medical and health sciences; Endopeptidases; Animals; Aspartic Acid Endopeptidases; Humans; Amyloid Precursor Protein Secretases; Copper; Molecular Chaperones

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.