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 Nterminal
segment upon association with membranes. In vitro the protein binds
avidly CuII, but in vivo the protein is N-acetylated, and CuII binding is lost. We
have now clarified the binding characteristics of the CuI 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 CuI-αS stoichiometry, where CuI is bound to Met1 and Met5 residues of
two helical peptide chains. The resulting tetrahedral CuI 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 CuI-αS, which retains
the capacity to activate O2 and promote oxidative reactions, membrane-bound
CuI-αS may serve as a sink for unreactive copper.