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General Description

spinqualitylabelsall models LARS (E coli) ternary complex with tRNAleu and leucyl adenylate analogue Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Leucyl tRNA synthetase (LARS) is a 97 kDa, class IA aminoacyl-tRNA synthetase (ARS) that catalyzes the ligation of leucine with tRNAleu in an ATP dependent mechanism. LARS is a cytoplasmic enzyme that is found as part of the multisynthetase complex in eukaryotes[1]. Multisynthetase complexes have also been seen in some archaea such as Thermococcus kodakarensis although the composition of the complex is not the same as eukaryotes[2]. LARS has been shown to be involved with the mTOR pathways as a sensor of leucine levels within the cell[3]. Mutations in LARS2, the mitochondrial version of the enzyme, have been linked to Perrault syndrome characterized by premature ovarian failure in females and progressive hearing loss in both sexes[4] Contents 1 Structure 1.1 Catalytic Domain 1.2 Editing Domain 1.3 Anticodon Binding Domain 2 Disease Structure Catalytic Domain The catalytic domain is responsible for the two step process of charging leucine on to tRNAleu. First, ATP and leucine are bound and AMP is transfered to the backbone carboxylic acid of leucine with the release of a pyrophosphate. Second, tRNAleu is bound with the leucyl adenylate and leucine is transfered to either the 2' or 3' OH of the 3' terminal adenine with the release of AMP. [5] [6] Editing Domain The editing domain of LARS is responsible for editing mischarged tRNA and ensuring translational fidelity. [7] [8] Anticodon Binding Domain The anticodon binding domain is essential for the fidelity of ARSs. However, there are numerous anticodons that correspond to leucine including AAU, GUA, and GUG Disease

3D Structure of LARS

Updated on 01-May-2018

References

1. ↑ Mirande M. The Aminoacyl-tRNA Synthetase Complex. Subcell Biochem. 2017;83:505-522. doi: 10.1007/978-3-319-46503-6_18. PMID:28271488 doi:http://dx.doi.org/10.1007/978-3-319-46503-6_18
2. ↑ Raina M, Elgamal S, Santangelo TJ, Ibba M. Association of a multi-synthetase complex with translating ribosomes in the archaeon Thermococcus kodakarensis. FEBS Lett. 2012 Jul 30;586(16):2232-8. doi: 10.1016/j.febslet.2012.05.039. Epub, 2012 Jun 7. PMID:22683511 doi:http://dx.doi.org/10.1016/j.febslet.2012.05.039
3. ↑ Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell. 2012 Apr 13;149(2):410-24. doi: 10.1016/j.cell.2012.02.044. Epub 2012 Mar, 15. PMID:22424946 doi:http://dx.doi.org/10.1016/j.cell.2012.02.044
4. ↑ Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, Klevit RE, King MC, Levy-Lahad E. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet. 2013 Apr 4;92(4):614-20. doi: 10.1016/j.ajhg.2013.03.007. Epub, 2013 Mar 28. PMID:23541342 doi:http://dx.doi.org/10.1016/j.ajhg.2013.03.007
5. ↑ Cusack S, Yaremchuk A, Tukalo M. The 2 A crystal structure of leucyl-tRNA synthetase and its complex with a leucyl-adenylate analogue. EMBO J. 2000 May 15;19(10):2351-61. PMID:10811626 doi:10.1093/emboj/19.10.2351
6. ↑ Palencia A, Crepin T, Vu MT, Lincecum TL Jr, Martinis SA, Cusack S. Structural dynamics of the aminoacylation and proofreading functional cycle of bacterial leucyl-tRNA synthetase. Nat Struct Mol Biol. 2012 Jun 10. doi: 10.1038/nsmb.2317. PMID:22683997 doi:10.1038/nsmb.2317
7. ↑ Seiradake E, Mao W, Hernandez V, Baker SJ, Plattner JJ, Alley MR, Cusack S. Crystal structures of the human and fungal cytosolic Leucyl-tRNA synthetase editing domains: A structural basis for the rational design of antifungal benzoxaboroles. J Mol Biol. 2009 Jul 10;390(2):196-207. Epub 2009 May 6. PMID:19426743 doi:10.1016/j.jmb.2009.04.073
8. ↑ Liu Y, Liao J, Zhu B, Wang ED, Ding J. Crystal structures of the editing domain of Escherichia coli leucyl-tRNA synthetase and its complexes with Met and Ile reveal a lock-and-key mechanism for amino acid discrimination. Biochem J. 2006 Mar 1;394(Pt 2):399-407. PMID:16277600 doi:10.1042/BJ20051249