Sequence determinants regulating fibrillation of human alpha-synuclein

Biochem Biophys Res Commun. 2008 Apr 11;368(3):772-8. doi: 10.1016/j.bbrc.2008.01.140. Epub 2008 Feb 7.


alpha-Synuclein is a neural protein that comprises the fibrillar core of Lewy bodies, a histologically defining lesion of Parkinson's disease. To investigate the role of each specific residue of the alpha-synuclein molecule in fibril formation, amino acid substitutions were introduced throughout the molecule. Incorporation of proline, especially in the region spanning residues 37-89, drastically retarded fibril formation. Substitutions with polar residues showed that the hydrophobicity of the central hydrophobic region is also important in fibrillation regulation. In the N-terminal repeated region, increasing the number of negative charges interfered with fibrillation. In contrast, single amino acid substitutions in the C-terminal acidic region of alpha-synuclein had only minimal effects on fibrillation. More than 20 different single amino acid substitutions that were sufficient to prevent fibrillation of alpha-synuclein were obtained, and most of them were impaired in both nucleation and fibril elongation. Identification of sequence determinants regulating fibrillation of amyloidogenic proteins may provide valuable information for designing peptide analog drugs to prevent protein amyloidosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Binding Sites
  • Computer Simulation
  • Dimerization
  • Humans
  • Models, Chemical*
  • Models, Molecular*
  • Molecular Sequence Data
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / ultrastructure
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • alpha-Synuclein / chemistry*
  • alpha-Synuclein / ultrastructure*


  • Amyloid
  • Multiprotein Complexes
  • alpha-Synuclein