Solid-state NMR reveals structural differences between fibrils of wild-type and disease-related A53T mutant alpha-synuclein

J Mol Biol. 2008 Jul 11;380(3):444-50. doi: 10.1016/j.jmb.2008.05.026. Epub 2008 May 17.

Abstract

Fibrils from the Parkinson's-disease-related A53T mutant of alpha-synuclein were investigated by solid-state NMR spectroscopy, electron microscopy, and atomic force microscopy. Sequential solid-state NMR resonance assignments were obtained for a large fraction of the fibril core. Experiments conducted above and below the freezing point suggest that the fibrils contain regions with increased mobility and structural elements different from beta-strand character, in addition to the rigid beta-sheet-rich core region. As in earlier studies on wild-type alpha-synuclein, the C-terminus was found to be flexible and unfolded, whereas the main core region was highly rigid and rich in beta-sheets. Compared to fibrils from wild-type alpha-synuclein, the well-ordered beta-sheet region extends to at least L38 and L100. These results demonstrate that a disease-related mutant of alpha-synuclein differs in both aggregation kinetics and fibril structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Escherichia coli / genetics
  • Freezing
  • Humans
  • Microscopy, Atomic Force
  • Microscopy, Electron
  • Molecular Sequence Data
  • Mutation*
  • Nuclear Magnetic Resonance, Biomolecular / methods*
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / ultrastructure
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / ultrastructure

Substances

  • Recombinant Proteins
  • alpha-Synuclein