Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation
Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation
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DOI：
10.1038/s41598-019-43926-9
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发表时间：
2019-05-16
影响因子：
4.6
通讯作者：
Hu, Hong-Yu
中科院分区：
文献类型：
--
作者：
Hong, Jun-Ye;Wang, Dong-Dong;Hu, Hong-Yu
Aaxin-7(Atx7)是一种与脊髓-小脑性共济失调7发病相关的疾病相关蛋白，其N-末端的多聚谷氨酰胺(PolyQ)是聚集和蛋白病变的病因源。我们用生化和生物物理方法研究了Atx7(Atx7-N)N端62个残基片段的结构、动力学和聚集特性。结果表明，正常的Atx7-N具有10个谷氨酸链(10q)，总体上呈柔性的无序结构，但在溶液中可能含有少量或较少的螺旋结构。多聚Q的扩张增加了多Q束的α-螺旋倾向，从而在淀粉样蛋白聚集过程中加强了它向β-折叠结构的转化。多聚Q链前面的丙氨酸富集区(ARR)形成了一个局部的相对稳定的a-螺旋。ArrA-螺旋可以启动和稳定随后的多聚Q链的螺旋形成，但它可能会抑制多聚Q扩展的Atx7-N在体外和细胞内的聚集。因此，Atx7-N中先前的ARR片段可能影响多聚体的动态结构和聚集特性，甚至决定致病多聚体长度的阈值。这项研究可能获得对Atx7淀粉样蛋白聚集的结构和动态的洞察力，并帮助我们进一步理解基于PolyQ扩展的Atx7蛋白病变。
Ataxin-7 (Atx7) is a disease-related protein associated with the pathogenesis of spinocerebellar ataxia 7, while its polyglutamine (polyQ) tract in N-terminus is the causative source of aggregation and proteinopathy. We investigated the structure, dynamics and aggregation properties of the N-terminal 62-residue fragment of Atx7 (Atx7-N) by biochemical and biophysical approaches. The results showed that the normal Atx7-N with a tract of 10 glutamines (10Q) overall adopts a flexible and disordered structure, but it may contain a short or small population of helical structure in solution. PolyQ expansion increases the a-helical propensity of the polyQ tract and consequently enhances its transformation into beta-sheet structures during amyloid aggregation. An alanine-rich region (ARR) just ahead of the polyQ tract forms a local and relatively stable a-helix. The ARR a-helix can initiate and stabilize helical formation of the following polyQ tract, but it may suppress aggregation of the polyQ-expanded Atx7-N both in vitro and in cell. Thus, the preceding ARR segment in Atx7-N may influence the dynamic structure and aggregation property of the polyQ tract and even determine the threshold of the pathogenic polyQ lengths. This study may gain structural and dynamic insights into amyloid aggregation of Atx7 and help us further understand the Atx7 proteinopathy based on polyQ expansion.