Conformational properties of α-synuclein in its free and lipid-associated states

α-Synuclein (αS) is a presynaptic terminal protein that is believed to play an important role in the pathogenesis of Parkinson’s disease (PD). We have used NMR spectroscopy to characterize the conformational properties of αS in solution as a free monomer and when bound to lipid vesicles and lipid-mimetic detergent micelles. Free wild-type αS is largely unfolded in solution, but exhibits a region with a preference for helical conformations that may be important in the aggregation of αS into fibrils. The N-terminal region of αS binds to synthetic lipid vesicles and detergent micelles in vitro and adopts a highly helical conformation, consistent with predictions based on sequence analysis. The C-terminal part of the protein does not associate with either vesicles or micelles, remaining free and unfolded. These results suggest that one function of αS may be to tether as of yet unidentified partners to lipid surfaces via interactions with its C-terminal tail