title: Structural intermediates during α-synuclein fibrillogenesis on phospholipid vesicles.
abstract: α-Synuclein (AS) fibrils are the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease and other related disorders. AS forms helices that bind phospholipid membranes with high affinity, but no atomic level data for AS aggregation in the presence of lipids is yet available. Here, we present direct evidence of a conversion from α-helical conformation to β-sheet fibrils in the presence of anionic phospholipid vesicles and direct conversion to β-sheet fibrils in their absence. We have trapped intermediate states throughout the fibril formation pathways to examine the structural changes using solid-state NMR spectroscopy and electron microscopy. The comparison between mature AS fibrils formed in aqueous buffer and those derived in the presence of anionic phospholipids demonstrates no major changes in the overall fibril fold. However, a site-specific comparison of these fibrillar states demonstrates major perturbations in the N-terminal domain with a partial disruption of the long β-strand located in the 40s and small perturbations in residues located in the "non-β amyloid component" (NAC) domain. Combining all these results, we propose a model for AS fibrillogenesis in the presence of phospholipid vesicles.
authors.affiliation: Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Gemma
authors.initials: G
authors.lastname: Comellas
authors.forename: Luisel R
authors.initials: LR
authors.lastname: Lemkau
authors.forename: Donghua H
authors.initials: DH
authors.lastname: Zhou
authors.forename: Julia M
authors.initials: JM
authors.lastname: George
authors.forename: Chad M
authors.initials: CM
authors.lastname: Rienstra
mesh_terms: D008854:Microscopy, Electron; D019906:Nuclear Magnetic Resonance, Biomolecular; D010743:Phospholipids / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D010743:Phospholipids; D051844:alpha-Synuclein