Priya S Binny, Gromiha M Michael
Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India.
Advanced Computational Drug Discovery Unit (ACDD), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan.
J Cell Biochem. 2019 Jun;120(6):10519-10529. doi: 10.1002/jcb.28338. Epub 2019 Jan 22.
Huntington disease is a neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) at the N-terminal of the huntingtin exon 1 protein. The detailed structure and the mechanism behind this aggregation remain unclear and it is assumed that the polyQ undergoes a conformational transition to the β-sheet structure when it aggregates. Investigating the misfolding of polyQ facilitates the determination of the molecular mechanism of aggregation and can potentially help in developing a novel approach to inhibit polyQ aggregation. Moreover, the flanking sequences of the polyQ region play a vital role in structural changes and the aggregation mechanism. We performed all-atom molecular dynamics simulations to gain structural insights into the aggregation mechanism using eight different models with glutamine repeat lengths Q , Q P , Q , Q , Q , Q , Q , and Q P . In the models without flanking polyPs, we noticed that the transformation of a random coil to β-sheet occurs when the number of Q increases. We also found that the flanking polyPs prevent aggregation by decreasing the probability of forming a β-sheet structure. When polyQ length increases, the 17 N-terminal flanking residues are more likely to adopt a β-sheet conformation from α-helix and coil. From our simulations, we suggest that at least 34 glutamines are required for initiating aggregation and 40 residues length is critical for the aggregation of huntingtin exon 1 protein for disease onset. This study provides structural insights into misfolding and the role of flanking sequences in huntingtin aggregation which will further help in developing therapeutic strategies for Huntington's disease.
亨廷顿舞蹈症是一种神经退行性疾病，由亨廷顿蛋白外显子1的N端多聚谷氨酰胺（polyQ）扩增引起。这种聚集背后的详细结构和机制仍不清楚，据推测，polyQ聚集时会发生构象转变为β-折叠结构。研究polyQ的错误折叠有助于确定聚集的分子机制，并可能有助于开发一种抑制polyQ聚集的新方法。此外，polyQ区域的侧翼序列在结构变化和聚集机制中起着至关重要的作用。我们进行了全原子分子动力学模拟，使用谷氨酰胺重复长度分别为Q、QP、Q、Q、Q、Q、Q和QP的八个不同模型，以深入了解聚集机制的结构。在没有侧翼多聚脯氨酸（polyP）的模型中，我们注意到当Q的数量增加时，无规卷曲会转变为β-折叠。我们还发现侧翼polyP通过降低形成β-折叠结构的概率来防止聚集。当polyQ长度增加时，17个N端侧翼残基更有可能从α-螺旋和无规卷曲转变为β-折叠构象。从我们的模拟中，我们认为至少需要34个谷氨酰胺才能引发聚集，40个残基的长度对于亨廷顿蛋白外显子1蛋白聚集导致疾病发作至关重要。这项研究提供了关于错误折叠以及侧翼序列在亨廷顿蛋白聚集中的作用的结构见解，这将进一步有助于开发针对亨廷顿舞蹈症的治疗策略。
