Explaining the structural plasticity of α-synuclein.
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.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, USA.
Orly
O
Ullman
Charles K
CK
Fisher
Collin M
CM
Stultz
D001499:Bayes Theorem; D002942:Circular Dichroism; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction; D051844:alpha-Synuclein / Q000737:chemistry*
D051844:alpha-Synuclein