Remodeling of Lipid Vesicles into Cylindrical Micelles by α-Synuclein in an Extended α-Helical Conformation

alpha-Synuclein (alpha S) is a protein with multiple conformations and interactions. Natively unfolded in solution, alpha S accumulates as amyloid in neurological tissue in Parkinson disease and interacts with membranes under both physiological and pathological conditions. Here, we used cryoelectron microscopy in conjunction with electron paramagnetic resonance (EPR) and other techniques to characterize the ability of alpha S to remodel vesicles. At molar ratios of 1: 5 to 1: 40 for protein/lipid (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol), large spherical vesicles are converted into cylindrical micelles similar to 50 angstrom in diameter. Other lipids of the same charge (negative) exhibit generally similar behavior, although bilayer tubes of 150-500 angstrom in width are also produced, depending on the lipid acyl chains. At higher protein/lipid ratios, discoid particles, 70-100 angstrom across, are formed. EPR data show that, on cylindrical micelles, alpha S adopts an extended amphipathic alpha-helical conformation, with its long axis aligned with the tube axis. The observed geometrical relationship between alpha S and the micelle suggests that the wedging of its long alpha-helix into the outer leaflet of a membrane may cause curvature and an anisotropic partition of lipids, leading to tube formation.