Oxidase Reactivity of CuII Bound to N-Truncated Aβ Peptides Promoted by Dopamine

The redox chemistry of copper(II) is strongly modulated by the coordination to amyloid-beta peptides and by the stability of the resulting complexes. Amino-terminal copper and nickel binding motifs (ATCUN) identified in truncated A beta sequences starting with Phe4 show very high affinity for copper(II) ions. Herein, we study the oxidase activity of [Cu-A beta(4-x)] and [Cu-A beta(1-x)] complexes toward dopamine and other catechols. The results show that the Cu-II-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-II-A beta-catechol] species determines the efficiency of the oxidation, although the reaction rate is ruled by reoxidation of the Cu-I complex. In addition to the N-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-A beta(4-x) reveal that the His-tandem is able to bind Cu-II ions independently of the ATCUN site, but the N-terminal metal complexation reduces the conformational mobility of the peptide chain, preventing the binding and oxidative reactivity toward catechol of Cu-II bound to the secondary site.

Automated summary

The redox chemistry of copper(II) is significantly influenced by its coordination with amyloid-beta peptides and the stability of resulting complexes. The study investigates the oxidase activity of Cu-Aβ complexes towards dopamine and catechols, revealing that Cu-II-ATCUN site is not redox-inert and catechol coordination induces metal reduction. Additionally, vicinal histidines provide a secondary Cu-binding motif independently of the ATCUN site, affecting the oxidative reactivity towards catechol.