DNA induces folding in alpha-synuclein: understanding the mechanism using chaperone property of osmolytes. Academic Article uri icon

Overview

abstract

  • Alpha-synuclein conformational modulation leading to fibrillation has been centrally implicated in Parkinson's disease. Previously, we have shown that alpha-synuclein has DNA binding property. In the present study, we have characterized the effect of DNA binding on the conformation and fibrillation kinetics of alpha-synuclein. It was observed that single-stranded circular DNA induce alpha-helix conformation in alpha-synuclein while plasmid supercoiled DNA has dual effect inducing a partially folded conformation and alpha-helix under different experimental conditions. Interestingly, alpha-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 alpha-synuclein promoted the fibrillation while DNA which induced alpha-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 alpha-synuclein was studied using effect of osmolytes on alpha-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 alpha-synuclein. The ability of DNA and osmolytes in inducing conformational transition in alpha-synuclein, indicates that two factors are critical in modulating alpha-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 alpha-helical conformation in alpha-synuclein and inhibiting the fibrillation may be of significance in engineering DNA-chip based therapeutic approaches to PD and other amyloid disorders.

publication date

  • April 26, 2007

Research

keywords

  • DNA
  • alpha-Synuclein

Identity

Scopus Document Identifier

  • 34447618598

Digital Object Identifier (DOI)

  • 10.1016/j.abb.2007.03.042

PubMed ID

  • 17537399

Additional Document Info

volume

  • 464

issue

  • 1