α-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling

There is increasing evidence for the involvement of lipid membranes in both the functional and pathological properties of alpha-synuclein (alpha-Syn). Despite many investigations to characterize the binding of alpha-Syn to membranes, there is still a lack of understanding of the binding mode linking the properties of lipid membranes to alpha-Syn insertion into these dynamic structures. Using a combination of an optical biosensing technique and in situ atomic force microscopy, we show that the binding strength of alpha-Syn is related to the specificity of the lipid environment (the lipid chemistry and steric properties within a bilayer structure) and to the ability of the membranes to accommodate and remodel upon the interaction of alpha-Syn with lipid membranes. We show that this interaction results in the insertion of alpha-Syn into the region of the headgroups, inducing a lateral expansion of lipid molecules that can progress to further bilayer remodeling, such as membrane thinning and expansion of lipids out of the membrane plane. We provide new insights into the affinity of alpha-Syn for lipid packing defects found in vesicles of high curvature and in planar membranes with cone-shaped lipids and suggest a comprehensive model of the interaction between alpha-Syn and lipid bilayers. The ability of alpha-Syn to sense lipid packing defects and to remodel membrane structure supports its proposed role in vesicle trafficking.