Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond
Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond
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人亮氨酰-tRNA合成酶在蛋白质合成及其他方面的多方面功能的分子基础
DOI：
10.1093/nar/gkaa189
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发表时间：
2020-05-21
影响因子：
14.9
通讯作者：
Wang, En-Duo
中科院分区：
文献类型：
--
作者：
Liu, Ru-Juan;Long, Tao;Wang, En-Duo
人胞浆亮氨酸- trna合成酶（hcLRS）是一种必需的多功能酶。它的典型功能是催化亮氨酸与tRNALeu的共价连接，也可能通过编辑机制水解错误的trna。它与其他8种氨基酰基- trna合成酶（AaRSs）和3种辅助蛋白一起形成一个大型的多合成酶复合物（MSC）。除了翻译作用外，hcLRS在雷帕霉素复合体1 （mTORC1）通路中还具有重要的亮氨酸传感器功能。由于这一途径在癌症发展中是活跃的，因此hcLRS是抗肿瘤药物开发的潜在靶点。此外，来自病原微生物的LRS已被证实是开发抗生素的药物靶点，但抗生素不应抑制hcLRS。在这里，我们以2.5 Å的分辨率展示了hcLRS的晶体结构，这是真核生物LRS的第一个完整结构，并分析了针对hcLRS不同位点的各种化合物的结合。我们还通过体外重组整个巨型复合物推断了hcLRS进入MSC的组装机制。总的来说，我们的研究为理解hcLRS的多方面功能和针对这些功能的药物开发提供了分子基础。
Abstract Human cytosolic leucyl-tRNA synthetase (hcLRS) is an essential and multifunctional enzyme. Its canonical function is to catalyze the covalent ligation of leucine to tRNALeu, and it may also hydrolyze mischarged tRNAs through an editing mechanism. Together with eight other aminoacyl-tRNA synthetases (AaRSs) and three auxiliary proteins, it forms a large multi-synthetase complex (MSC). Beyond its role in translation, hcLRS has an important moonlight function as a leucine sensor in the rapamycin complex 1 (mTORC1) pathway. Since this pathway is active in cancer development, hcLRS is a potential target for anti-tumor drug development. Moreover, LRS from pathogenic microbes are proven drug targets for developing antibiotics, which however should not inhibit hcLRS. Here we present the crystal structure of hcLRS at a 2.5 Å resolution, the first complete structure of a eukaryotic LRS, and analyze the binding of various compounds that target different sites of hcLRS. We also deduce the assembly mechanism of hcLRS into the MSC through reconstitution of the entire mega complex in vitro. Overall, our study provides the molecular basis for understanding both the multifaceted functions of hcLRS and for drug development targeting these functions.