Probing Conformational Change of Intrinsically Disordered α-Synuclein to Helical Structures by Distinctive Regional Interactions with Lipid Membranes

alpha-Synuclein (alpha-Syn) is an intrinsically disordered protein, whose fibrillar aggregates are associated with the pathogenesis of Parkinson's disease. alpha-Syn associates with lipid membranes and forms helical structures upon membrane binding. In this study, we explored the helix formation of alpha-Syn in solution containing trifluoroethanol using small-angle X-ray scattering and electrospray ionization ion mobility mass spectrometry. We then investigated the structural transitions of alpha-Syn to helical structures via association with large unilamellar vesicles as model lipid membrane systems. Hydrogen deuterium exchange combined with electrospray ionization mass spectrometry was further utilized to understand the details of the regional interaction mechanisms of alpha-Syn with lipid vesicles based on the polarity of the lipid head groups. The characteristics of the helical structures were observed with alpha-Syn by adsorption onto the anionic phospholipid vesicles via electrostatic interactions between the N-terminal region of the protein and the anionic head groups of the lipids. alpha-Syn also associates with zwitterionic lipid vesicles and forms helical structures via hydrophobic interactions. These experimental observations provide an improved understanding of the distinct structural change mechanisms of alpha-Syn that originate from different regional interactions of the protein with lipid membranes and subsequently provide implications regarding diverse protein-membrane interactions related to their fibrillation kinetics.