Controlling aggregation propensity in A53T mutant of alpha-synuclein causing Parkinson's disease

Biochem Biophys Res Commun. 2009 Sep 18;387(2):305-9. doi: 10.1016/j.bbrc.2009.07.008. Epub 2009 Jul 4.

Abstract

Understanding alpha-synuclein in terms of fibrillization, aggregation, solubility and stability is fundamental in Parkinson's disease (PD). The three familial mutations, namely, A30P, E46K and A53T cause PD because the hydrophobic regions in alpha-synuclein acquire beta-sheet configuration, and have a propensity to fibrillize and form amyloids that cause cytotoxicity and neurodegeneration. On simulating the native form and mutants (A30P, E46K and A53T) of alpha-synuclein in water solvent, clear deviations are observed in comparison to the all-helical 1XQ8 PDB structure. We have identified two crucial residues, (40)Val and (74)Val, which play key roles in beta-sheet aggregation in the hydrophobic regions 36-41 and 68-78, respectively, leading to fibrillization and amyloidosis in familial (A53T) PD. We have also identified V40D_V74D, a double mutant of A53T (the most amyloidogenic mutant). The simultaneous introduction of these two mutations in A53T nearly ends its aggregation propensity, increases its solubility and positively enhances its thermodynamic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Humans
  • Mutation
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Protein Stability
  • Protein Structure, Secondary
  • Solubility
  • Thermodynamics
  • Valine / chemistry
  • Valine / genetics
  • Valine / metabolism*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • alpha-Synuclein
  • Valine