Abstract

The ?-amyloid precursor protein (?-APP) contains a copper-binding site localized between amino acids 135 and 156 (?-APP135-156). We have employed synthetic ?-APP peptides to characterize their capacities to reduce Cu(II) to Cu(I). Analogues of the wild-type ?-APP135-156 peptide, containing specific amino acid substitutions, were used to establish which residues are specifically involved in the reduction of copper by ?- APP135-156. We report here that ?-APP's copper-binding domain reduced Cu(II) to Cu(I). The single-mutant ?-APP(His147?Ala) and the double-mutant ?-APP(His147?Ala/His149?Ala) showed a small decrease in copper reduction in relation to the wild-type peptide and the ?-APP(Cys144?Ser) mutation abolished it, suggesting that Cys144 is the key amino acid in the oxidoreduction reaction. Our results confirm that soluble ?-APP is involved in the reduction of Cu(II) to Cu(I).