Oxidase Reactivity of Cu^II Bound to <i>N</i>-Truncated Aβ Peptides Promoted by Dopamine

• Main Authors: Chiara Bacchella, Simone Dell’Acqua, Stefania Nicolis, Enrico Monzani, Luigi Casella
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: International Journal of Molecular Sciences
• Subjects: copper; amyloid-β peptides; Alzheimer’s disease; oxidative stress; dopamine; neurodegeneration
• Online Access: https://www.mdpi.com/1422-0067/22/10/5190

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_4−x] and [Cu–Aβ_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–Aβ–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 <i>N</i>-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_4−x reveal that the His-tandem is able to bind Cu^II ions independently of the ATCUN site, but the <i>N</i>-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.