Copper(I) Forms a Redox-Stable 1:2 Complex with α-Synuclein N-Terminal Peptide in a Membrane-Like Environment.
α-Synuclein (αS) is the main protein component of Lewy bodies, characterizing the pathogenesis of Parkinson's disease. αS is unstructured in solution but adopts a helical structure in its extended N-terminal segment upon association with membranes. In vitro the protein binds avidly Cu(II), but in vivo the protein is N-acetylated, and Cu(II) binding is lost. We have now clarified the binding characteristics of the Cu(I) complex with the truncated αS peptide 1-15, both in N-acetylated and free amine forms, in a membrane mimetic environment and found that complexation occurs with a 1:2 Cu(I)-αS stoichiometry, where Cu(I) is bound to Met1 and Met5 residues of two helical peptide chains. The resulting tetrahedral Cu(I) center is redox-stable, does not form reactive oxygen species, and is unreactive against dopamine in the presence of O2. This suggests that, unlike cytosolic Cu(I)-αS, which retains the capacity to activate O2 and promote oxidative reactions, membrane-bound Cu(I)-αS may serve as a sink for unreactive copper.
Dipartimento di Chimica, Università di Pavia , Via Taramelli 12, 27100 Pavia, Italy.
Simone
S
Dell'Acqua
Dipartimento di Chimica, Università di Pavia , Via Taramelli 12, 27100 Pavia, Italy.
Valentina
V
Pirota
Dipartimento di Chimica, Università di Pavia , Via Taramelli 12, 27100 Pavia, Italy.
Enrico
E
Monzani
Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
Francesca
F
Camponeschi
Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
Riccardo
R
De Ricco
Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
Daniela
D
Valensin
Dipartimento di Chimica, Università di Pavia , Via Taramelli 12, 27100 Pavia, Italy.
Luigi
L
Casella
D003300:Copper / Q000737:chemistry*; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry*
D010455:Peptides; D051844:alpha-Synuclein; D003300:Copper