The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence.
The La-related protein 1-specific domain repurposes HEAT-like repeats to directly bind a 5'TOP sequence.
复制标题
与LA相关的蛋白1特异性结构域重新调整热重复以直接结合5'TOP序列。
DOI：
10.1093/nar/gkv748
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发表时间：
2015-09-18
影响因子：
14.9
通讯作者：
Berman AJ
中科院分区：
文献类型：
--
作者：
Lahr RM;Mack SM;Héroux A;Blagden SP;Bousquet-Antonelli C;Deragon JM;Berman AJ
LA相关蛋白1(LA-Related Protein 1，LARP1)调节多种mRNAs的稳定性。这些包括5‘TOPS，mTOR-激酶反应的mRNAs和富含嘧啶的5’UTRs，它们编码核糖体蛋白和翻译因子。我们确定人LARP1的高度保守的特定于LARP1的C末端DM15区域直接与5‘端序列结合。这个DM15区域的晶体结构细化到1.86ä分辨率，在每个单体中有三个结构相关和进化保守的螺旋-转角-螺旋模块。这些基序类似于热重复序列，即普遍存在的螺旋蛋白结合结构，但它们的序列与已知的热模块的一致序列不一致，表明这种结构已被重新用于RNA相互作用。推测的mTORC1-识别序列位于这些重复的灵活环C-末端。我们还介绍了在DM15区域高度保守的表面上富含嘧啶的单链RNA的建模。这些研究为LARP1将mTOR信号与核糖体生物发生联系起来的结构机制奠定了必要的基础。
La-related protein 1 (LARP1) regulates the stability of many mRNAs. These include 5′TOPs, mTOR-kinase responsive mRNAs with pyrimidine-rich 5′ UTRs, which encode ribosomal proteins and translation factors. We determined that the highly conserved LARP1-specific C-terminal DM15 region of human LARP1 directly binds a 5′TOP sequence. The crystal structure of this DM15 region refined to 1.86 Å resolution has three structurally related and evolutionarily conserved helix-turn-helix modules within each monomer. These motifs resemble HEAT repeats, ubiquitous helical protein-binding structures, but their sequences are inconsistent with consensus sequences of known HEAT modules, suggesting this structure has been repurposed for RNA interactions. A putative mTORC1-recognition sequence sits within a flexible loop C-terminal to these repeats. We also present modelling of pyrimidine-rich single-stranded RNA onto the highly conserved surface of the DM15 region. These studies lay the foundation necessary for proceeding toward a structural mechanism by which LARP1 links mTOR signalling to ribosome biogenesis.