title: Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.
abstract: The intrinsically disordered protein alpha-synuclein plays a key role in the pathogenesis of Parkinson's disease (PD). We show here that the native state of alpha-synuclein consists of a broad distribution of conformers with an ensemble-averaged hydrodynamic radius significantly smaller than that expected for a random coil structure. This partial condensation is driven by interactions between the highly charged C-terminus and a large hydrophobic central region of the protein sequence. We suggest that this structure could inhibit the formation of alpha-synuclein aggregates, which are thought to be the cytotoxic species responsible for neurodegeneration in PD.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Dedmon
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011487:Protein Conformation; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D008024:Ligands; D009419:Nerve Tissue Proteins; D051843:Synucleins; D051844:alpha-Synuclein