DNA induces folding in α-synuclein: Understanding the mechanism using chaperone property of osmolytes

Muralidhar Hegde, K. S.J. Rao

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

α-Synuclein conformational modulation leading to fibrillation has been centrally implicated in Parkinson's disease. Previously, we have shown that α-synuclein has DNA binding property. In the present study, we have characterized the effect of DNA binding on the conformation and fibrillation kinetics of α-synuclein. It was observed that single-stranded circular DNA induce α-helix conformation in α-synuclein while plasmid supercoiled DNA has dual effect inducing a partially folded conformation and α-helix under different experimental conditions. Interestingly, α-synuclein showed a specificity for GC* nucleotide sequence in its binding ability to DNA. The aggregation kinetics data showed that DNA which induced partially folded conformation in α-synuclein promoted the fibrillation while DNA which induced α-helix delayed the fibrillation, indicating that the partially folded intermediate conformation is critical in the aggregation process. Further, the mechanism of DNA-induced folding/aggregation of α-synuclein was studied using effect of osmolytes on α-synuclein as a model system. Among the five osmolytes used, Glycerol, trimethylamine-N-oxide, Betaine, and Taurine induced partially folded conformation and in turn enhanced the aggregation of α-synuclein. The ability of DNA and osmolytes in inducing conformational transition in α-synuclein, indicates that two factors are critical in modulating α-synuclein folding: (i) electrostatic interaction as in the case of DNA, and (ii) hydrophobic interactions as in the case of osmolytes. The property of DNA inducing α-helical conformation in α-synuclein and inhibiting the fibrillation may be of significance in engineering DNA-chip based therapeutic approaches to PD and other amyloid disorders.

Original languageEnglish (US)
Pages (from-to)57-69
Number of pages13
JournalArchives of Biochemistry and Biophysics
Volume464
Issue number1
DOIs
StatePublished - Aug 1 2007

Keywords

  • α-Synuclein
  • α-Synuclein aggregation
  • Neurodegeneration
  • Omolytes
  • Parkinson's disease
  • Protein folding

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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