Oxidase Reactivity of Cu Bound to -Truncated Aβ Peptides Promoted by Dopamine.

The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-β peptides and by the stability of the resulting complexes. Amino-terminal copper and nickel binding motifs (ATCUN) identified in truncated Aβ sequences starting with Phe4 show very high affinity for copper(II) ions. Herein, we study the oxidase activity of [Cu-Aβ] and [Cu-Aβ] complexes toward dopamine and other catechols. The results show that the Cu-ATCUN site is not redox-inert; the reduction of the metal is induced by coordination of catechol to the metal and occurs through an inner sphere reaction. The generation of a ternary [Cu-Aβ-catechol] species determines the efficiency of the oxidation, although the reaction rate is ruled by reoxidation of the Cu complex. In addition to the -terminal coordination site, the two vicinal histidines, His13 and His14, provide a second Cu-binding motif. Catechol oxidation studies together with structural insight from the mixed dinuclear complexes Ni/Cu-Aβ reveal that the His-tandem is able to bind Cu ions independently of the ATCUN site, but the -terminal metal complexation reduces the conformational mobility of the peptide chain, preventing the binding and oxidative reactivity toward catechol of Cu bound to the secondary site.