| Structural highlights
Disease
GARS_HUMAN Autosomal dominant Charcot-Marie-Tooth disease type 2D;Distal hereditary motor neuropathy type 5. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
GARS_HUMAN Catalyzes the ATP-dependent ligation of glycine to the 3'-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565, PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a universal pleiotropic signaling molecule needed for cell regulation pathways, by direct condensation of 2 ATPs. Thereby, may play a special role in Ap4A homeostasis (PubMed:19710017).[1] [2] [3] [4]
Publication Abstract from PubMed
Glycyl-tRNA synthetase (GlyRS) is the enzyme that covalently links glycine to cognate tRNA for translation. It is of great research interest because of its nonconserved quaternary structures, unique species-specific aminoacylation properties, and noncanonical functions in neurological diseases, but none of these is fully understood. We report two crystal structures of human GlyRS variants, in the free form and in complex with tRNA(Gly) respectively, and reveal new aspects of the glycylation mechanism. We discover that insertion 3 differs considerably in conformation in catalysis and that it acts like a "switch" and fully opens to allow tRNA to bind in a cross-subunit fashion. The flexibility of the protein is supported by molecular dynamics simulation, as well as enzymatic activity assays. The biophysical and biochemical studies suggest that human GlyRS may utilize its flexibility for both the traditional function (regulate tRNA binding) and alternative functions (roles in diseases).
Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis.,Deng X, Qin X, Chen L, Jia Q, Zhang Y, Zhang Z, Lei D, Ren G, Zhou Z, Wang Z, Li Q, Xie W J Biol Chem. 2016 Mar 11;291(11):5740-52. doi: 10.1074/jbc.M115.679126. Epub 2016, Jan 21. PMID:26797133[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Cader MZ, Ren J, James PA, Bird LE, Talbot K, Stammers DK. Crystal structure of human wildtype and S581L-mutant glycyl-tRNA synthetase, an enzyme underlying distal spinal muscular atrophy. FEBS Lett. 2007 Jun 26;581(16):2959-64. Epub 2007 May 29. PMID:17544401 doi:10.1016/j.febslet.2007.05.046
- ↑ Guo RT, Chong YE, Guo M, Yang XL. Crystal structures and biochemical analyses suggest a unique mechanism and role for human glycyl-tRNA synthetase in Ap4A homeostasis. J Biol Chem. 2009 Oct 16;284(42):28968-76. Epub 2009 Aug 26. PMID:19710017 doi:10.1074/jbc.M109.030692
- ↑ Qin X, Hao Z, Tian Q, Zhang Z, Zhou C, Xie W. Cocrystal Structures of Glycyl-tRNA Synthetase in Complex with tRNA Suggest Multiple Conformational States in Glycylation. J Biol Chem. 2014 Jul 18;289(29):20359-69. doi: 10.1074/jbc.M114.557249. Epub, 2014 Jun 4. PMID:24898252 doi:http://dx.doi.org/10.1074/jbc.M114.557249
- ↑ Oprescu SN, Chepa-Lotrea X, Takase R, Golas G, Markello TC, Adams DR, Toro C, Gropman AL, Hou YM, Malicdan MCV, Gahl WA, Tifft CJ, Antonellis A. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation. Hum Mutat. 2017 Oct;38(10):1412-1420. doi: 10.1002/humu.23287. Epub 2017 Jul 14. PMID:28675565 doi:http://dx.doi.org/10.1002/humu.23287
- ↑ Deng X, Qin X, Chen L, Jia Q, Zhang Y, Zhang Z, Lei D, Ren G, Zhou Z, Wang Z, Li Q, Xie W. Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis. J Biol Chem. 2016 Mar 11;291(11):5740-52. doi: 10.1074/jbc.M115.679126. Epub 2016, Jan 21. PMID:26797133 doi:http://dx.doi.org/10.1074/jbc.M115.679126
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