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mRNA-STAR 结构域相互作用的机制：哺乳动物 Quaking STAR 蛋白的分子动力学模拟。

Mechanism of mRNA-STAR domain interaction: Molecular dynamics simulations of Mammalian Quaking STAR protein.

机构信息

Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Sector 81, Knowledge City, SAS Nagar, Punjab, India.

出版信息

Sci Rep. 2017 Oct 3;7(1):12567. doi: 10.1038/s41598-017-12930-2.

DOI:10.1038/s41598-017-12930-2
PMID:28974714
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5626755/
Abstract

STAR proteins are evolutionary conserved mRNA-binding proteins that post-transcriptionally regulate gene expression at all stages of RNA metabolism. These proteins possess conserved STAR domain that recognizes identical RNA regulatory elements as YUAAY. Recently reported crystal structures show that STAR domain is composed of N-terminal QUA1, K-homology domain (KH) and C-terminal QUA2, and mRNA binding is mediated by KH-QUA2 domain. Here, we present simulation studies done to investigate binding of mRNA to STAR protein, mammalian Quaking protein (QKI). We carried out conventional MD simulations of STAR domain in presence and absence of mRNA, and studied the impact of mRNA on the stability, dynamics and underlying allosteric mechanism of STAR domain. Our unbiased simulations results show that presence of mRNA stabilizes the overall STAR domain by reducing the structural deviations, correlating the 'within-domain' motions, and maintaining the native contacts information. Absence of mRNA not only influenced the essential modes of motion of STAR domain, but also affected the connectivity of networks within STAR domain. We further explored the dissociation of mRNA from STAR domain using umbrella sampling simulations, and the results suggest that mRNA binding to STAR domain occurs in multi-step: first conformational selection of mRNA backbone conformations, followed by induced fit mechanism as nucleobases interact with STAR domain.

摘要

STAR 蛋白是进化上保守的 mRNA 结合蛋白，可在后转录水平调控 RNA 代谢的各个阶段的基因表达。这些蛋白具有保守的 STAR 结构域，可识别与 YUAAY 相同的 RNA 调控元件。最近报道的晶体结构表明，STAR 结构域由 N 端的 QUA1、K 同源结构域（KH）和 C 端的 QUA2 组成，mRNA 结合由 KH-QUA2 结构域介导。在这里，我们进行了模拟研究，以研究 mRNA 与 STAR 蛋白，哺乳动物 Quaking 蛋白（QKI）的结合。我们对 STAR 结构域在存在和不存在 mRNA 的情况下进行了常规 MD 模拟，并研究了 mRNA 对 STAR 结构域稳定性、动力学和潜在变构机制的影响。我们的无偏模拟结果表明，mRNA 的存在通过减少结构偏差、相关“域内”运动以及保持天然接触信息来稳定整个 STAR 结构域。没有 mRNA 不仅影响 STAR 结构域的基本运动模式，还影响 STAR 结构域内网络的连通性。我们进一步使用伞状采样模拟探索了 mRNA 从 STAR 结构域的解离，结果表明 mRNA 与 STAR 结构域的结合是多步骤的：首先是 mRNA 骨架构象的构象选择，然后是核碱基与 STAR 结构域相互作用的诱导契合机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/5281eb850970/41598_2017_12930_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/62dc257b65bd/41598_2017_12930_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/f3d1aff151a2/41598_2017_12930_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/8a2834428a74/41598_2017_12930_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/8d808369fc90/41598_2017_12930_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/28739599f985/41598_2017_12930_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/85b8908e73c1/41598_2017_12930_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/2ffb78c32fd1/41598_2017_12930_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/5281eb850970/41598_2017_12930_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/62dc257b65bd/41598_2017_12930_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/f3d1aff151a2/41598_2017_12930_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/8a2834428a74/41598_2017_12930_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/8d808369fc90/41598_2017_12930_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/28739599f985/41598_2017_12930_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/85b8908e73c1/41598_2017_12930_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/2ffb78c32fd1/41598_2017_12930_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b43b/5626755/5281eb850970/41598_2017_12930_Fig8_HTML.jpg

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