DNA induces folding in alpha-synuclein: understanding the mechanism using chaperone property of osmolytes.
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.
Hegde
Muralidhar L
ML
Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore 570020, India.
Rao
K S J
KS
D000818:Animals; D001622:Betaine / Q000737:chemistry; D002417:Cattle; D004247:DNA / Q000737:chemistry*; D004270:DNA, Circular / Q000737:chemistry; D004277:DNA, Single-Stranded / Q000737:chemistry; D005990:Glycerol / Q000737:chemistry; D008744:Methylamines / Q000737:chemistry; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D017433:Protein Structure, Secondary; D012521:Sarcosine / Q000737:chemistry; D013654:Taurine / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D004270:DNA, Circular; D004277:DNA, Single-Stranded; D008744:Methylamines; D018832:Molecular Chaperones; D051844:alpha-Synuclein; D013654:Taurine; D001622:Betaine; D004247:DNA; C005855:trimethyloxamine; D005990:Glycerol; D012521:Sarcosine