title: Role of N-terminal methionine residues in the redox activity of copper bound to alpha-synuclein.
abstract: Amyloid aggregation of α-synuclein (AS) is one of the hallmarks of Parkinson's disease. The interaction of copper ions with the N-terminal region of AS promotes its amyloid aggregation and metal-catalyzed oxidation has been proposed as a plausible mechanism. The AS(1-6) fragment represents the minimal sequence that models copper coordination to this intrinsically disordered protein. In this study, we evaluated the role of methionine residues Met1 and Met5 in Cu(II) coordination to the AS(1-6) fragment, and in the redox activity of the Cu-AS(1-6) complex. Spectroscopic and electronic structure calculations show that Met1 may play a role as an axial ligand in the Cu(II)-AS(1-6) complex, while Met5 does not participate in metal coordination. Cyclic voltammetry and reactivity studies demonstrate that Met residues play an important role in the reduction and reoxidation processes of this complex. However, Met1 plays a more important role than Met5, as substitution of Met1 by Ile decreases the reduction potential of the Cu-AS(1-6) complex by ~80 mV, causing a significant decrease in its rate of reduction. Reoxidation of the complex by oxygen results in oxidation of the Met residues to sulfoxide, being Met1 more susceptible to copper-catalyzed oxidation than Met5. The sulfoxide species can suffer elimination of methanesulfenic acid, rendering a peptide with no thioether moiety, which would impair the ability of AS to bind Cu(I) ions. Overall, our study underscores the important roles that Met1 plays in copper coordination and the reactivity of the Cu-AS complex.
authors.affiliation: Department of Chemistry, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, 07360, Mexico City, Mexico.
authors.forename: Esaú E
authors.initials: EE
authors.lastname: Rodríguez
authors.affiliation: Department of Chemistry, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, 07360, Mexico City, Mexico.
authors.forename: Trinidad
authors.initials: T
authors.lastname: Arcos-López
authors.affiliation: Department of Chemistry, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, 07360, Mexico City, Mexico.
authors.forename: Lidia G
authors.initials: LG
authors.lastname: Trujano-Ortiz
authors.affiliation: Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Ocampo y Esmeralda, S2002LRK, Rosario, Argentina.
authors.forename: Claudio O
authors.initials: CO
authors.lastname: Fernández
authors.affiliation: Department of Chemistry, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, 07360, Mexico City, Mexico.
authors.forename: Felipe J
authors.initials: FJ
authors.lastname: González
authors.affiliation: Department of Chemistry, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, 07360, Mexico City, Mexico.
authors.forename: Alberto
authors.initials: A
authors.lastname: Vela
authors.affiliation: Department of Chemistry, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, 07360, Mexico City, Mexico. lilianaq@cinvestav.mx.
authors.forename: Liliana
authors.initials: L
authors.lastname: Quintanar
mesh_terms: D003300:Copper / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008715:Methionine / Q000737:chemistry*; D015394:Molecular Structure; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D051844:alpha-Synuclein; D003300:Copper; D008715:Methionine
keywords: Alpha-synuclein; Circular dichroism; Copper; DFT; EPR; Electronic structure