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), but the role of lipid-binding in α-synuclein’s propensity to aggregate is not fully understood. Here, we explore how a mathematical framework reveals details in protein-membrane interactions that are disrupted by PD-associated mutants. Upon binding, α-synuclein forms two α-helices that insert into the lipid membrane – a process that is mediated by lipid membrane defects. Through a tryptophan fluorescence assay, we reveal how the binding of these two helices are differentially affected by PD-associated mutants, altering the equilibrium distribution of fully vs. partially bound protein. In unraveling the role of α-synuclein in the progression of PD, we reveal a unifying difference in protein behavior between wild-type α-synuclein and disease-associated mutants.

Parkinson’s Disease-associated mutations in α-synuclein disrupt equilibrium bound states of the protein’s two helices  </i>

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.