E46K Parkinson's-linked mutation enhances C-terminal-to-N-terminal contacts in alpha-synuclein

J Mol Biol. 2009 May 22;388(5):1022-32. doi: 10.1016/j.jmb.2009.03.065. Epub 2009 Apr 5.

Abstract

Parkinson's disease (PD) is associated with the deposition of fibrillar aggregates of the protein alpha-synuclein (alphaS) in neurons. Intramolecular contacts between the acidic C-terminal tail of alphaS and its N-terminal region have been proposed to regulate alphaS aggregation, and two originally described PD mutations, A30P and A53T, reportedly reduce such contacts. We find that the most recently discovered PD-linked alphaS mutation E46K, which also accelerates the aggregation of the protein, does not interfere with C-terminal-to-N-terminal contacts and instead enhances such contacts. Furthermore, we do not observe a substantial reduction in such contacts in the two previously characterized mutants. Our results suggest that C-terminal-to-N-terminal contacts in alphaS are not strongly protective against aggregation, and that the dominant mechanism by which PD-linked mutations facilitate alphaS aggregation may be altering the physicochemical properties of the protein such as net charge (E46K) and secondary structure propensity (A30P and A53T).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Mutagenesis, Site-Directed
  • Mutation*
  • Nuclear Magnetic Resonance, Biomolecular
  • Parkinson Disease / genetics*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Structure, Secondary / genetics*
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism

Substances

  • Peptide Fragments
  • alpha-Synuclein