DNA induces folding in α-synuclein:: Understanding the mechanism using chaperone property of osmolytes
DNA induces folding in α-synuclein:: Understanding the mechanism using chaperone property of osmolytes
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DOI：
10.1016/j.abb.2007.03.042
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发表时间：
2007-08-01
影响因子：
3.9
通讯作者：
Rao, K. S. J.
中科院分区：
文献类型：
--
作者：
Hegde, Muralidhar L.;Rao, K. S. J.
导致纤颤的a-突触核蛋白构象调节被认为与帕金森病有中心关系。在此之前，我们已经证明-突触核蛋白具有DNA结合特性。在本研究中，我们描述了DNA结合对a-突触核蛋白构象和纤颤动力学的影响。在不同的实验条件下，单链环状DNA在a-synuclein中诱导a-helix构象，而质粒超螺旋DNA在a-synuclein中诱导部分折叠构象和a-helix构象具有双重作用。有趣的是，a-synuclein与DNA的结合能力对GC*核苷酸序列具有特异性。聚集动力学数据表明，诱导α -突触蛋白部分折叠构象的DNA促进了纤颤，而诱导a-螺旋的DNA延缓了纤颤的发生，说明部分折叠的中间构象在纤颤聚集过程中起着关键作用。进一步，以渗透物对α -突触核蛋白的作用为模型系统，研究了dna诱导α -突触核蛋白折叠/聚集的机制。在使用的五种渗透解液中，甘油、三甲胺- n -氧化物、甜菜碱和牛磺酸诱导部分折叠构象，进而增强a-酰基络合物的聚集。DNA和渗透分子诱导α -突触核蛋白构象转变的能力表明，有两个因素对调节α -突触核蛋白折叠至关重要：(1)静电相互作用（如DNA）和(2)疏水相互作用（如渗透分子）。DNA诱导α -突触核蛋白a-螺旋构象和抑制纤颤的特性可能对基于DNA芯片的PD和其他淀粉样蛋白疾病的工程治疗方法具有重要意义。(c) 2007爱思唯尔公司版权所有。
a-Synuclein conformational modulation leading to fibrillation has been alpha 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 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 alpha-symiclein 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 alpha-synuclein was studied using effect of osmolytes on alpha-symiclein 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-symiclein. The ability of DNA and osmolytes in inducing conformational transition in alpha-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 alpha-synuclein and inhibiting the fibrillation may be of significance in engineering DNA-chip based therapeutic approaches to PD and other amyloid disorders. (c) 2007 Elsevier Inc. All rights reserved.