The N-terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

PLoS One. 2015 Feb 13;10(2):e0116497. doi: 10.1371/journal.pone.0116497. eCollection 2015.

Abstract

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA:α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dopamine / metabolism*
  • Humans
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Protein Multimerization*
  • Protein Structure, Secondary
  • Proteolysis
  • Solubility
  • Trypsin / metabolism
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / metabolism

Substances

  • Peptide Fragments
  • alpha-Synuclein
  • Trypsin
  • Dopamine

Grants and funding

Funding provided by National Health and Medical Research Council of Australia, Program Grant 628946. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.