La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs
La-related protein 1 (LARP1) binds the mRNA cap, blocking eIF4F assembly on TOP mRNAs
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DOI：
10.7554/elife.24146
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发表时间：
2017-04-07
期刊：
影响因子：
7.7
通讯作者：
Berman, Andrea J.
中科院分区：
文献类型：
--
作者：
Lahr, Roni M.;Fonseca, Bruno D.;Berman, Andrea J.
5′末端寡嘧啶（5TOP）基序是一种顺式调控RNA元件，位于编码核糖体蛋白和翻译因子的TOP mRNA的7 - 甲基鸟苷[m7G]帽的紧邻下游。在真核生物中，该基序协调翻译机制中蛋白质组分的同步和化学计量表达。La相关蛋白1（LARP1）与TOP mRNA结合，调节其稳定性和翻译。我们展示了人LARP1的DM15区域分别与5′TOP基序、帽类似物（m7GTP）以及带帽胞苷（m(7)GpppC）形成复合物的晶体结构，分辨率分别为2.6埃、1.8埃和1.7埃。我们的结合、竞争和免疫沉淀数据证实并详细阐述了LARP1与5TOP基序结合的机制。我们表明LARP1直接结合TOP mRNA的帽以及相邻的5TOP基序，有效地阻碍eIF4E接近帽并阻止eIF4F组装。因此，LARP1是一种专门的TOP mRNA帽结合蛋白，可控制核糖体的生物发生。
The 5terminal oligopyrimidine (5TOP) motif is a cis-regulatory RNA element located immediately downstream of the 7-methylguanosine [m7G] cap of TOP mRNAs, which encode ribosomal proteins and translation factors. In eukaryotes, this motif coordinates the synchronous and stoichiometric expression of the protein components of the translation machinery. La-related protein 1 (LARP1) binds TOP mRNAs, regulating their stability and translation. We present crystal structures of the human LARP1 DM15 region in complex with a 5'TOP motif, a cap analog (m7GTP), and a capped cytidine (m(7)GpppC), resolved to 2.6, 1.8 and 1.7 angstrom, respectively. Our binding, competition, and immunoprecipitation data corroborate and elaborate on the mechanism of 5TOP motif binding by LARP1. We show that LARP1 directly binds the cap and adjacent 5TOP motif of TOP mRNAs, effectively impeding access of eIF4E to the cap and preventing eIF4F assembly. Thus, LARP1 is a specialized TOP mRNA cap-binding protein that controls ribosome biogenesis.