The mode of α-synuclein binding to membranes depends on lipid composition and lipid to protein ratio

Interactions of the presynaptic protein α-synuclein with membranes are involved in its physiological action as well as in the pathological misfolding and aggregation related to Parkinsons’s disease. We studied the conformation and orientation of α-synuclein bound to model vesicular membranes using multiparametric response polarity-sensitive fluorescent probes together with CD and EPR measurements. At low lipid to α-synuclein ratio the protein binds membranes through its N-terminal domain. When lipids are in excess, the α-helical content and the role of the C-terminus in binding increase. Highly rigid membranes also induce a greater α-helical content and a lower polarity of the protein microenvironment.

► The conformation and orientation of α-synuclein on membrane depend on bilayer properties.
► The binding to the lipid bilayer does not require complete formation of an α-helical region.
► At low lipid/protein ratio α-synuclein interacts with membranes primarily through its N-terminus.