Cysteine 144 is a key residue in the copper reduction by the beta-amyloid precursor protein

The beta-amyloid precursor protein (beta-APP) contains a copper-binding sit e localized between amino acids 135 and 156 (beta-APP(135-156)). We have em ployed synthetic beta-APP peptides to characterize their capacities to redu ce Cu(II) to Cu(I). Analogues of the wild-type beta-APP(135-156) peptide, c ontaining specific amino acid substitutions, were used to establish which r esidues are specifically involved in the reduction of copper by beta-APP(13 5-156). We report here that beta-APP's copper-binding domain reduced Cu(II) to Cu(I). The single-mutant beta-APP(His147-->Ala) and the double-mutant b eta-APP(His147-->Ala/His149-->Ala) showed a small decrease in copper reduct ion in relation to the wild-type peptide and the beta-APP(Cys144-->Ser) mut ation abolished it, suggesting that Cys144 is the key amino acid in the oxi doreduction reaction. Our results confirm that soluble beta-APP is involved in the reduction of Cu(II) to Cu(I).