Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations.
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.
Dedmon
Matthew M
MM
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Lindorff-Larsen
Kresten
K
Christodoulou
John
J
Vendruscolo
Michele
M
Dobson
Christopher M
CM
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
D008024:Ligands; D009419:Nerve Tissue Proteins; D051843:Synucleins; D051844:alpha-Synuclein