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

Muralidhar, L. Hegde and Rao, K.S.J. (2007) DNA induces folding in a-synuclein: Understanding the mechanism using chaperone property of osmolytes. Archives of Biochemistry and Biophysics, 464 . pp. 57-69.

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Abstract

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

Item Type:	Article
Uncontrolled Keywords:	Parkinson’s disease; a-Synuclein; Protein folding; a-Synuclein aggregation; Omolytes; Neurodegeneration
Subjects:	600 Technology > 01 Medical sciences
Divisions:	Dept. of Biochemistry
Depositing User:	Food Sci. & Technol. Information Services
Date Deposited:	20 Nov 2008 07:11
Last Modified:	28 Dec 2011 10:06
URI:	http://ir.cftri.res.in/id/eprint/8850

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