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Abstract

alpha-Synuclein (alpha S) is a membrane-binding protein with sequence similarity to apolipoproteins and other lipid-carrying proteins, which are capable of forming lipid-containing nanoparticles, sometimes referred to as "discs." Previously, it has been unclear whether alpha S also possesses this property. Using cryo-electron microscopy and light scattering, we found that alpha S can remodel phosphatidylglycerol vesicles into nanoparticles whose shape (ellipsoidal) and dimensions (in the 7-10-nm range) resemble those formed by apolipoproteins. The molar ratio of alpha S to lipid in nanoparticles is similar to 1:20, and alpha S is oligomeric (including trimers and tetramers). Similar nanoparticles form when alpha S is added to vesicles of mitochondrial lipids. This observation suggests a mechanism for the previously reported disruption of mitochondrial membranes by alpha S. Circular dichroism and four-pulse double electron electron resonance experiments revealed that in nanoparticles alpha S assumes a broken helical conformation distinct from the extended helical conformation adopted when alpha S is bound to intact vesicles or membrane tubules. We also observed alpha S-dependent tubule and nanoparticle formation in the presence of oleic acid, implying that alpha S can interact with fatty acids and lipids in a similar manner. alpha S-related nanoparticles might play a role in lipid and fatty acid transport functions previously attributed to this protein.