Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations |
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Authors: | Dedmon Matthew M Lindorff-Larsen Kresten Christodoulou John Vendruscolo Michele Dobson Christopher M |
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Institution: | Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. |
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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. |
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