Understanding the remodeling of lipid bilayers induced by binding of alpha-Synucl

University Of Minnesota, Minneapolis MN

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Abstract

DESCRIPTION (provided by applicant): ?-Synuclein (?S) is a 140 amino acid, intrinsically disordered protein that adopts an amphipathic ?-helical structure upon binding the membrane. ?S is the major proteinaceous component of insoluble fibrillar Lewy bodies, a hallmark of Parkinson's disease (PD). The precise roles of both native and pathological forms of ?S remain unclear. However, the interaction of ?S with cellular membranes is now thought to be critical to its native function, and potentially to its role in PD as well. We propose a series of Low-Angle X-ray Scattering (LAXS) experiments and molecular dynamics (MD) simulations to more fully understand the membrane remodeling effects of native ?S. We will be primarily focused on the role of lipid composition and bilayer curvature. In particular, we propose the following two specific aims, each of which will be carried out in parallel: 1) Determine how ?S remodels membranes when bound to both monolayer leaflets. 2) Determine how ?S remodels membranes when bound to only one leaflet, modeling its physiological action on synaptic vesicles. Each of these aims will test our hypothesis that the intrinsic, natural curvature of ?S dictates its capacity to remodel and stabilize membranes, in particular those that are highly curved (like synaptic vesicles).