α-synuclein regulates neurotransmitter release by binding to the outer lipid membrane of synaptic vesicles. Mutations within the lipid-binding region of α-synuclein are associated with protein aggregation and progression of Parkinson’s Disease (PD). Upon binding, α-synuclein forms an α-helix that partially inserts into the lipid membrane – a process that is mediated by lipid membrane defects. However, mutations within this lipid-binding region can disrupt the formation of the helix and alter the equilibrium bound state of the protein. Here, we identify how mutations within this region of α-synuclein affect the protein’s search for a binding site on a lipid membrane. Through a tryptophan fluorescence assay, we systematically examine how each mutant modifies α-helix formation and how, in turn, this alters the identity of a lipid binding site. In unraveling the role of α-synuclein in the progression of PD, we use a joint analysis of affinity and the identity of a “binding site” to characterize protein-membrane interactions. In doing so, we reveal a unifying difference in protein behavior between wild-type α-synuclein and disease-associated mutants.

Disease-associated mutations in α-synuclein affect binding-site identity and affinity for lipid-membranes

ACS Spring 2022

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