α-synuclein interactions with lipid membranes

Abstract: α-synuclein is an intrinsically disordered protein implicated in synaptic vesicle trafficking at the synapse. Accumulation of α-synuclein in the form of amyloid deposits coincides with the loss of dopaminergic neurons in Parkinsons disease. These deposits, referred to as Lewy Bodies, have been shown to contain membrane lipids together with the α-synuclein amyloid fibrils and other proteins. It was also shown that lipid membranes can interfere with the process of α-synuclein amyloid formation. Thus, interactions with lipids are believed to be core to both the healthy as well as the aberrant function of α-synuclein and studies of these interactions may shed light on the mechanisms of the processes occurring both in health and in disease.In this work, α-synuclein interactions with model lipid membranes were studied across a wide range of relative protein and lipid concentrations including excess protein and excess membrane conditions. The exchange rate between the free and membrane-bound protein was estimated to be between 20 and 100 s−1. The association of the protein with membranes was characterized as strongly positively cooperative. Several different α-synuclein membrane-binding modes were identified and the factors influencing which binding mode dominates at given conditions were determined. α-synuclein-induced remodeling of lipid membranes was also studied and it was shown that protein adsorption increases the curvature of the membrane. Lipids were shownto modulate the kinetics of α-synuclein amyloid formation and to be incorporated into the formed structures.