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首页> 外文期刊>Biochemistry >Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10)
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Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10)

机译：AUUCU重复RNA引起脊髓小脑性共济失调10型（SCA10）的晶体学和计算分析

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摘要

Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 angstrom and analysis of the structure via molecular dynamics simulations. The r(AUUCU) tracts adopt an overall A-form geometry in which 3 x 3 nucleotide (5)'UCU3'/(UCU5')-U-3' internal loops are closed by AU pairs. Helical parameters of the refined structure as well as the corresponding electron density map on the crystallographic model reflect dynamic features of the internal loop. The computational analyses captured dynamic motion of the loop closing pairs, which can form single-stranded conformations with relatively low energies. Overall, the results presented here suggest the possibility for r(AUUCU) repeats to form metastable A-from structures, which can rearrange into single-stranded conformations and attract proteins such as heterogeneous nuclear ribonucleoprotein K (hnRNP K). The information presented here may aid in the rational design of therapeutics targeting this RNA.
机译：脊髓小脑共济失调10型（SCA10）是由ATXN10 pre-mRNA内含子9中r（AUUCU）的五核苷酸重复扩增引起的。 RNA通过一种功能获得机制引起疾病，该机制可以使参与RNA生物发生的蛋白质失活。光谱研究表明，r（AUUCU）重复形成发夹结构。但是，在此之前没有高分辨率的结构模型。在这里，我们报告模型r（AUUCU）的第一个晶体结构重复精制到2.8埃，并通过分子动力学模拟对该结构进行分析。 r（AUUCU）区域采用整体A形几何结构，其中3 x 3个核苷酸（5）'UCU3'/（UCU5'）-U-3'内部环被AU对封闭。精制结构的螺旋参数以及晶体学模型上的相应电子密度图反映了内部回路的动态特征。计算分析捕获了闭环对的动态运动，可以形成具有相对较低能量的单链构象。总的来说，这里提出的结果表明r（AUUCU）重复形成亚稳A-结构的可能性，该结构可以重排成单链构象并吸引蛋白质，例如异质核糖核蛋白K（hnRNP K）。此处提供的信息可能有助于合理设计靶向该RNA的疗法。

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