Synucleins and apolipoproteins have been implicated in a number of membrane and lipid trafficking events. Lipid interaction for both types of proteins is mediated by 11 amino acid repeats that form amphipathic helices. This similarity suggests that synucleins and apolipoproteins might have comparable effects on lipid membranes, but this has not been shown directly. Here, we find that ␣-synuclein, -synuclein, and apolipoprotein A-1 have the conserved functional ability to induce membrane curvature and to convert large vesicles into highly curved membrane tubules and vesicles. The resulting structures are morphologically similar to those generated by amphiphysin, a curvature-inducing protein involved in endocytosis. Unlike amphiphysin, however, synucleins and apolipoproteins do not require any scaffolding domains and curvature induction is mediated by the membrane insertion and wedging of amphipathic helices alone. Moreover, we frequently observed that ␣-synuclein caused membrane structures that had the appearance of nascent budding vesicles. The ability to function as a minimal machinery for vesicle budding agrees well with recent findings that ␣-synuclein plays a role in vesicle trafficking and enhances endocytosis. Induction of membrane curvature must be under strict regulation in vivo; however, as we find it can also cause disruption of membrane integrity. Because the degree of membrane curvature induction depends on the concerted action of multiple proteins, controlling the local protein density of tubulating proteins may be important. How cellular safeguarding mechanisms prevent such potentially toxic events and whether they go awry in disease remains to be determined.
Background: Membrane fusion and fission events are effected by remodeling proteins. Results: Using cryoelectron microscopy, we observed the conversion of large spherical lipid vesicles into narrow protein-coated tubes. Conclusion: Tubulation is accompanied by ␣-synuclein switching into an extended ␣-helical conformation. Significance: The cylindrical micelles produced resemble a hemi-fission/fusion state of the membrane.
The process of neurodegeneration in Parkinson’s Disease is intimately associated with the aggregation of the protein α-synuclein into toxic oligomers and fibrils. Interestingly, many of these protein aggregates are found to be posttranslationally modified by ubiquitin at several different lysine residues. However, the inability to generate homogeneously ubiquitin modified α-synuclein at each site has prevented the understanding of the specific biochemical consequences. We have used protein semi-synthesis to generate nine site-specifically ubiquitin modified α-synuclein derivatives and have demonstrated that different ubiquitination sites have differential effects on α-synuclein aggregation.
Background:Parkinson disease protein ␣-synuclein has sequence similarity with apolipoproteins. Results: ␣-Synuclein can generate nanoparticles from phospholipid membranes and fatty acids by taking up a broken helical structure. Conclusion: These nanoparticles have shapes and dimensions reminiscent of apolipoprotein nanodiscs. Significance: The data suggest apolipoprotein-like roles for ␣-synuclein as a lipid-or fatty acid-carrying protein.
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