Explaining the Structural Plasticity of α-Synuclein
Author(s)Ullman, Orly; Fisher, Charles K.; Stultz, Collin M.
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Given that α-synuclein has been implicated in the pathogenesis of several neurodegenerative disorders, deciphering the structure of this protein is of particular importance. While monomeric α-synuclein is disordered in solution, it can form aggregates rich in cross-β structure, relatively long helical segments when bound to micelles or lipid vesicles, and a relatively ordered helical tetramer within the native cell environment. To understand the physical basis underlying this structural plasticity, we generated an ensemble for monomeric α-synuclein using a Bayesian formalism that combines data from NMR chemical shifts, RDCs, and SAXS with molecular simulations. An analysis of the resulting ensemble suggests that a non-negligible fraction of the ensemble (0.08, 95% confidence interval 0.03–0.12) places the minimal toxic aggregation-prone segment in α-synuclein, NAC(8–18), in a solvent exposed and extended conformation that can form cross-β structure. Our data also suggest that a sizable fraction of structures in the ensemble (0.14, 95% confidence interval 0.04–0.23) contains long-range contacts between the N- and C-termini. Moreover, a significant fraction of structures that contain these long-range contacts also place the NAC(8–18) segment in a solvent exposed orientation, a finding in contrast to the theory that such long-range contacts help to prevent aggregation. Lastly, our data suggest that α-synuclein samples structures with amphipathic helices that can self-associate via hydrophobic contacts to form tetrameric structures. Overall, these observations represent a comprehensive view of the unfolded ensemble of monomeric α-synuclein and explain how different conformations can arise from the monomeric protein.
DepartmentHarvard University--MIT Division of Health Sciences and Technology; Massachusetts Institute of Technology. Department of Chemistry; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science; Massachusetts Institute of Technology. Research Laboratory of Electronics
Journal of the American Chemical Society
American Chemical Society (ACS)
Ullman, Orly, Charles K. Fisher, and Collin M. Stultz. “Explaining the Structural Plasticity of α-Synuclein.” Journal of the American Chemical Society 133.48 (2011): 19536–19546. © 2011 American Chemical Society
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