A copper-binding site in the cytoplasmic domain of BACE1 identifies a possible link to metal homoeostasis and oxidative stress in Alzheimer's disease.
The amyloidogenic processing pathway of the APP (amyloid precursor protein) generates Abeta (amyloid beta-peptide), the major constituent in Alzheimer's disease senile plaques. This processing is catalysed by two unusual membrane-localized aspartic proteinases, beta-secretase [BACE1 (beta-site APP-cleaving enzyme 1)] and the gamma-secretase complex. There is a clear link between APP processing and copper homoeostasis in the brain. APP binds copper and zinc in the extracellular domain and Abeta also binds copper, zinc and iron. We have found that a 24-residue peptide corresponding to the C-terminal domain of BACE1 binds a single copper(I) atom with high affinity through cysteine residues. We also observed that the cytoplasmic domain of BACE1 interacts with CCS, the dedicated copper chaperone for SOD1 (superoxide dismutase 1). Overproduction of BACE1 reduces SOD1 activity in cells. Consequently, SOD1 activity, cytosolic copper and ectodomain cleavage of APP are linked through BACE1.
Dingwall
C
C
Pharmaceutical Sciences Research Division, King's College London, Franklin-Wilkins Building, Stamford Street, London SE1 9NH, UK. Colin.Dingwall@kcl.ac.uk
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D066298:In Vitro Techniques; D008670:Metals / Q000378:metabolism; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C114678:CCS protein, human; D008670:Metals; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C000606290:SOD1 protein, human; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human