Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond
| Autor: | Ru-Juan Liu, Hao Li, En-Duo Wang, Stephen Cusack, JingHua Zhao, Jing Li, Jinzhong Lin, MingZhu Wang, Andrés Palencia, Tao Long |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular RNA Transfer Leu AcademicSubjects/SCI00010 RNA-binding protein Biology 010402 general chemistry 01 natural sciences 03 medical and health sciences Anti-Infective Agents Protein Domains Catalytic Domain Genetics Humans Molecular Biology Monomeric GTP-Binding Proteins 030304 developmental biology 0303 health sciences Leucyl-tRNA synthetase Leucine—tRNA ligase Translation (biology) 0104 chemical sciences Biochemistry Drug development Drug Design Amino Acyl-tRNA Synthetases Transfer RNA Biocatalysis Leucine-tRNA Ligase Transfer RNA Aminoacylation Function (biology) |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkaa189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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