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Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond.

Liu RJ, Long T, Li H, Zhao J, Li J, Wang M, Palencia A, Lin J, Cusack S, Wang ED
Nucleic Acids Res 48 4946-4959 (2020)
Cited: 9 times
EuropePMC logo PMID: 32232361

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.

Articles - 6lpf mentioned but not cited (4)

  1. Molecular basis of the multifaceted functions of human leucyl-tRNA synthetase in protein synthesis and beyond. Liu RJ, Long T, Li H, Zhao J, Li J, Wang M, Palencia A, Lin J, Cusack S, Wang ED. Nucleic Acids Res 48 4946-4959 (2020)
  2. Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase. Chen B, Luo S, Zhang S, Ju Y, Gu Q, Xu J, Yang XL, Zhou H. Nat Commun 12 1616 (2021)
  3. Tissue-specific alternative splicing separates the catalytic and cell signaling functions of human leucyl-tRNA synthetase. Baymiller M, Nordick B, Forsyth CM, Martinis SA. J Biol Chem 298 101757 (2022)
  4. Design, Synthesis and Antimicrobial Evaluation of New N-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)(hetero)aryl-2-carboxamides as Potential Inhibitors of Mycobacterial Leucyl-tRNA Synthetase. Šlechta P, Needle AA, Jand'ourek O, Paterová P, Konečná K, Bárta P, Kuneš J, Kubíček V, Doležal M, Kučerová-Chlupáčová M. Int J Mol Sci 24 2951 (2023)


Reviews citing this publication (1)

  1. Aminoacyl-tRNA synthetases of the multi-tRNA synthetase complex and their role in tumorigenesis. Khan K, Gogonea V, Fox PL. Transl Oncol 19 101392 (2022)

Articles citing this publication (4)

  1. Eukaryotic tRNA sequences present conserved and amino acid-specific structural signatures. Westhof E, Thornlow B, Chan PP, Lowe TM. Nucleic Acids Res 50 4100-4112 (2022)
  2. Multimodal cotranslational interactions direct assembly of the human multi-tRNA synthetase complex. Khan K, Long B, Gogonea V, Deshpande GM, Vasu K, Fox PL. Proc Natl Acad Sci U S A 119 e2205669119 (2022)
  3. New insights into hallux valgus by whole exome sequencing study. Jia J, Li J, Qu H, Li M, Zhang S, Hao J, Gao X, Meng X, Sun Y, Hakonarson H, Zeng X, Xia Q, Li J. Exp Biol Med (Maywood) 246 1607-1616 (2021)
  4. Adenosine-Dependent Activation Mechanism of Prodrugs Targeting an Aminoacyl-tRNA Synthetase. Hoffmann G, Le Gorrec M, Mestdach E, Cusack S, Salmon L, Jensen MR, Palencia A. J Am Chem Soc 145 800-810 (2023)


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