Cysteine 144 Is a Key Residue in the Copper Reduction by the β‐Amyloid Precursor Protein

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Abstract
: The β-amyloid precursor protein (β-APP) contains a copper-binding site localized between amino acids 135 and 156 (β-APP135-156). We have employed synthetic β-APP peptides to characterize their capacities to reduce Cu(II) to Cu(I). Analogues of the wild-type β-APP135-156 peptide, containing specific amino acid substitutions, were used to establish which residues are specifically involved in the reduction of copper by β-APP135-156. We report here that β-APP’s copper-binding domain reduced Cu(II) to Cu(I). The single-mutant β-APPHis147→Ala and the double-mutant β-APPHis147→Ala/His149→Ala showed a small decrease in copper reduction in relation to the wild-type peptide and the β-APPSys144→Ser mutation abolished it, suggesting that Cys144 is the key amino acid in the oxidoreduction reaction. Our results confirm that soluble β-APP is involved in the reduction of Cu(II) to Cu(I).