Parkinson's disease-associated mutations in α-synuclein alters its lipid-bound state.

Lipid-binding properties of α-synuclein play a central role in protein aggregation and progression of Parkinson's disease (PD). α-Synuclein, an intrinsically disordered protein, binds to lipid membranes through the formation of two amphipathic helices that insert into the lipid bilayer. All disease-associated single point mutations have been identified to be within these helical regions of α-synuclein: V15A, A30P, E46K, H50Q, G51D, A53T, and A53V. However, the effects of these mutations on the bound states of the two α helices of the protein have yet to be fully characterized. In this report, we use a tryptophan fluorescence assay to measure the binding of the α helices of these PD-associated mutants to lipid membranes within the lipid-depletion regime. We characterize the binding behavior of each helix, revealing that, generally, the PD-associated mutants shift the equilibrium bound state away from the N-terminal helix of the protein toward helix 2 at lower lipid concentrations. Altogether, our results indicate that disruption to the equilibrium binding of the two α helices of α-synuclein could play a role in PD progression.