(608b) Molecular Mechanisms of Membrane Curvature Sensing and Generation By Alpha Synuclein

Alpha-synuclein (α-syn) is an intrinsically disordered protein (IDP) that is abundant in neurons, where it is implicated in the pathogenesis of Parkinson’s disease through cytosolic aggregation and formation of fibrils. In its healthy state, α-syn binds to synaptic lipid vesicles, transitioning to a membrane-inserting, α-helical structure in its N-terminal region while the C-terminal domain remains disordered in close proximity to the membrane. These types of disordered C-terminal domains have been shown to amplify and/or generate membrane curvature for several proteins through steric and/or electrostatic interactions with the membrane, which is essential for cellular function. However, little is known about the role of this disordered C-terminal domain in α-syn. In this study, we utilize quantitative, in vitro microscopy and circular dichroism spectroscopy to examine both equilibrium and dynamic binding of α-syn to curved membranes, as well as the ability α-syn to induce fission in synthetic membranes. When the C-terminal domain of α-syn is neutralized, its ability to sense and generate curvature is reduced substantially. Our results suggest that an electrostatic mechanism may dictate the protein-lipid interactions between membrane-bound α-syn and biological membranes. This work unveils biologically relevant functionality that was previously unexplored and poorly understood for a disordered protein.