Alpha-synuclein (aS) is a small presynaptic protein implicated in the pathogenesis of Parkinsons disease. It partitions between an intrinsically disordered cytosolic state and a more structured vesicle-bound state. Structural studies of αS have, to date, been based largely on the SDS detergent-bound conditions, for which αS displays α-helices in the N-terminal domain and an unstructured C-terminal tail that remains free in solution. We have investigated the structure and biophysics of αS in the presence of lipid bicelles. Lipid bicelles offer the advantage of a natural lipid bilayer while also featuring small vesicle radii which render them amenable to solution NMR studies. Our biophysical and NMR data show that αS displays a preference for specific combinations of acidic and zwitterionic lipid headgroups and give evidence that αS participates in dynamic exchange processes on the lipid bilayer that may reorganize the bilayer with time. Additionally, our results show that this lipid interaction of αS is coupled with effects on aggregation propensity. For full length αS, lipid bicelles greatly enhance aggregation, producing well-ordered, fibrillar structures. The lipid-induced aggregation is even more strongly stimulated for a C-terminal deletion construct of α-synuclein.
