Effects of nitration on the structure and aggregation of α-synuclein

Vladimir N. Uversky, Ghiam Yamin, Larissa A. Munishkina, Mikhail A. Karymov, Ian S. Millett, Sebastian Doniach, Yuri L. Lyubchenko, Anthony L. Fink

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

Substantial evidence suggests that the aggregation of the presynaptic protein α-synuclein is a key step in the etiology of Parkinson's disease (PD). Although the molecular mechanisms underlying α-synuclein aggregation remain unknown, oxidative stress has been implicated in the pathogenesis of PD. Here, we report the effects of tyrosine nitration on the propensity of human recombinant α-synuclein to fibrillate in vitro. The properties of nitrated α-synuclein were investigated using a variety of biophysical and biochemical techniques, which revealed that nitration led to formation of a partially folded conformation with increased secondary structure relative to the intrinsically disordered structure of the monomer, and to oligomerization at neutral pH. The degree of self-association was concentration-dependent, but at 1 mg/mL, nitrated α-synuclein was predominantly an octamer. At low pH, small-angle X-ray scattering data indicated that the nitrated protein was monomeric. α-Synuclein fibrillation at neutral pH was completely inhibited by nitrotyrosination and is attributed to the formation of stable soluble oligomers. The presence of heparin or metals did not overcome the inhibition; however, the inhibitory effect was eliminated at low pH. The addition of nitrated α-synuclein inhibited fibrillation of non-modified α-synuclein at neutral pH. Potential implications of these findings to the etiology of Parkinson's disease are discussed.

Original languageEnglish (US)
Pages (from-to)84-102
Number of pages19
JournalMolecular Brain Research
Volume134
Issue number1
DOIs
StatePublished - Mar 24 2005
Externally publishedYes

Keywords

  • Aggregation
  • Amyloid fibrils
  • Inhibition of fibrillation
  • Natively unfolded protein
  • Nitration
  • Oxidative stress
  • Partially folded intermediate
  • α-synuclein

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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