Membrane Remodeling by α-Synuclein and Effects on Amyloid Formation

摘要

α-Synudein (α-Syn), an intrinsically disordered protein, is associated with Parkinson's disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by α-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter ~20 nm). No discernible secondary structural changes were detected by circular dichroism spectroscopy upon the addition of vesicles. Notably, membrane remodeling inhibits α-syn amyloid formation affecting both lag and growth phases. Using five single tryptophan variants and time-resolved fluorescence anisotropy measurements, we determined that a-syn influences bilayer structure with surprisingly weak interaction and no site specificity (partition constant, K_p ~ 300 M~(-1)). Vesicle deformation by a-syn under a variety of different lipid/protein conditions is characterized via transmission electron microscopy. As cellular membranes are enriched in PC lipids, these results support possible biological consequences for a-syn induced membrane remodeling related to both function and pathogenesis.