Copper Binding and Redox Activity of α-Synuclein in Membrane-Like Environment

alpha-Synuclein (alpha Syn) constitutes the main protein component of Lewy bodies, which are the pathologic hallmark in Parkinson's disease. alpha Syn is unstructured in solution but the interaction of alpha Syn with lipid membrane modulates its conformation by inducing an alpha-helical structure of the N-terminal region. In addition, the interaction with metal ions can trigger alpha Syn conformation upon binding and/or through the metal-promoted generation of reactive oxygen species which lead to a cascade of structural alterations. For these reasons, the ternary interaction between alpha Syn, copper, and membranes needs to be elucidated in detail. Here, we investigated the structural properties of copper-alpha Syn binding through NMR, EPR, and XAS analyses, with particular emphasis on copper(I) coordination since the reduced state is particularly relevant for oxygen activation chemistry. The analysis was performed in different membrane model systems, such as micellar sodium dodecyl sulfate (SDS) and unilamellar vesicles, comparing the binding of full-length alpha Syn and N-terminal peptide fragments. The presence of membrane-like environments induced the formation of a copper:alpha Syn = 1:2 complex where Cu+ was bound to the Met1 and Met5 residues of two helical peptide chains. In this coordination, Cu+ is stabilized and is unreactive in the presence of O-2 in catechol substrate oxidation.