The C‐Terminal Domain of α‐Synuclein Confers Steric Stabilization on Synaptic Vesicle‐Like Surfaces

Abstract

While -Synuclein, an intrinsically disordered protein linked to Parkinson's disease, has been shown to associate with membrane organelles, its overall cellular function remains nebulous. -Synuclein binds to membranes through its amino-terminal domain (first ~ 100 residues), but there is no This article is protected by copyright. All rights reserved. 2 consensus on the biophysical function of the carboxyl-terminal domain (last ~ 40 residues) due, in part, to its lack of strong interaction partners and persisting intrinsic disorder even when membranebound. Here, by directly applying force on -Synuclein bound to spherical nanoparticle-supported lipid bilayers (SSLBs) and tracking higher-order structural changes through small-angle X-ray scattering, we present strong evidence that -Synuclein sterically stabilizes membrane surfaces through its carboxyl-terminal domain. Full-length -Synuclein dramatically increases the critical osmotic pressure at which SSLBs cluster (P C ~ 1.3 x 10 5 Pa) compared to -Synuclein without the carboxyl-terminal domain (P C ~ 1.9 x 10 4 Pa) at physiological salt and temperature conditions. We show this clustering of -Synuclein-bound SSLBs to be reversible and sensitive to monovalent/divalent salt, both features of grafted polyelectrolyte-mediated steric stabilization. In elucidating the biophysical function of -Synuclein in the framework of polymer science, we demonstrate that the carboxyl-terminal domain can potentially utilize its persisting intrinsic disorder to functionalize membrane surfaces.

An Emerging Role for Phosphoinositides in the Pathophysiology of Parkinson’s Disease

“…It has been suggested that the membrane binding domain in ␣-Syn senses membrane curvature; facilitates the formation or stabilizes a curvature on membrane structures [105]; or forms a tether between vesicles [101]. The acidic C-terminal region in ␣-Syn has been suggested to support and sterically stabilize curved membrane structures [106]. In accord with these reports, a role for ␣-Syn in the maintenance [107,108] and dynamics of SV pools has been reported [109,110].…”