Glycine—tRNA ligase

Glycine—tRNA ligase also known as glycyl–tRNA synthetase is an enzyme that in humans is encoded by the GARS1 gene.[5][6][7]

Glycine—tRNA ligase
Identifiers
EC no.6.1.1.14
CAS no.9037-62-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
GARS1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGARS1, CMT2D, DSMAV, GlyRS, HMN5, SMAD1, glycyl-tRNA synthetase, GARS, glycyl-tRNA synthetase 1, HMN5A, SMAJI
External IDsOMIM: 600287 MGI: 2449057 HomoloGene: 1547 GeneCards: GARS1
Orthologs
SpeciesHumanMouse
Entrez

2617

353172

Ensembl

ENSG00000106105

ENSMUSG00000029777

UniProt

P41250

Q9CZD3

RefSeq (mRNA)

NM_002047
NM_001316772

NM_180678

RefSeq (protein)

NP_001303701
NP_002038

NP_851009

Location (UCSC)Chr 7: 30.58 – 30.63 MbChr 6: 55.01 – 55.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases.[7]

Reaction

In enzymology, a glycine—tRNA ligase (EC 6.1.1.14) is an enzyme that catalyzes the chemical reaction

ATP + glycine + tRNAGly AMP + diphosphate + glycyl-tRNAGly

The 3 substrates of this enzyme are ATP, glycine, and tRNA(Gly), whereas its 3 products are AMP, diphosphate, and glycyl-tRNA(Gly).

This enzyme belongs to the family of ligases, to be specific those forming carbon-oxygen bonds in aminoacyl-tRNA and related compounds. The systematic name of this enzyme class is glycine:tRNAGly ligase (AMP-forming). Other names in common use include glycyl-tRNA synthetase, glycyl-transfer ribonucleate synthetase, glycyl-transfer RNA synthetase, glycyl-transfer ribonucleic acid synthetase, and glycyl translase. This enzyme participates in glycine, serine and threonine metabolism and aminoacyl-trna biosynthesis.

Interactions

Glycyl-tRNA synthetase has been shown to interact with EEF1D.[8] Mutant forms of the protein associated with peripheral nerve disease have been shown to aberrantly bind to the transmembrane receptor proteins neuropilin 1[9] and Trk receptors A-C.[10]

Clinical relevance

Glycyl-tRNA synthetase has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis.[7]

The peripheral nerve diseases Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) have been liked to dominant mutations in GARS.[11][12] CMT2D usually manifests during the teenage years, and results in muscle weakness predominantly in the hands and feet.[13] Two mouse models of CMT2D have been used to better understand the disease, identifying that the disorder is caused by a toxic gain-of-function of the mutant glycine-tRNA ligase protein.[14] The CMT2D mice display peripheral nerve axon degeneration [15][16] and defective development[17] and function[18]> of the neuromuscular junction.

References
  1. GRCh38: Ensembl release 89: ENSG00000106105 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000029777 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Nichols RC, Pai SI, Ge Q, Targoff IN, Plotz PH, Liu P (Nov 1995). "Localization of two human autoantigen genes by PCR screening and in situ hybridization--glycyl-tRNA synthetase locates to 7p15 and alanyl-tRNA synthetase locates to 16q22". Genomics. 30 (1): 131–2. doi:10.1006/geno.1995.0028. PMID 8595897.
  6. Ionasescu V, Searby C, Sheffield VC, Roklina T, Nishimura D, Ionasescu R (Sep 1996). "Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D)". Human Molecular Genetics. 5 (9): 1373–5. CiteSeerX 10.1.1.588.4502. doi:10.1093/hmg/5.9.1373. PMID 8872480.
  7. "Entrez Gene: GARS glycyl-tRNA synthetase".
  8. Sang Lee J, Gyu Park S, Park H, Seol W, Lee S, Kim S (Feb 2002). "Interaction network of human aminoacyl-tRNA synthetases and subunits of elongation factor 1 complex". Biochemical and Biophysical Research Communications. 291 (1): 158–64. doi:10.1006/bbrc.2002.6398. PMID 11829477.
  9. He W, Bai G, Zhou H, Wei N, White NM, Lauer J, Liu H, Shi Y, Dumitru CD, Lettieri K, Shubayev V, Jordanova A, Guergueltcheva V, Griffin PR, Burgess RW, Pfaff SL, Yang XL (2015). "CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase". Nature. 526 (7575): 710–4. Bibcode:2015Natur.526..710H. doi:10.1038/nature15510. PMC 4754353. PMID 26503042.
  10. Sleigh JN, Dawes JM, West SJ, Wei N, Spaulding EL, Gómez-Martín A, Zhang Q, Burgess RW, Cader MZ, Talbot K, Yang XL, Bennett DL, Schiavo G (2017). "Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations". Proc Natl Acad Sci U S A. 114 (16): E3324–E3333. doi:10.1073/pnas.1614557114. PMC 5402433. PMID 28351971.
  11. Motley WW, Talbot K, Fischbeck KH (Feb 2010). "GARS axonopathy: not every neuron's cup of tRNA". Trends in Neurosciences. 33 (2): 59–66. doi:10.1016/j.tins.2009.11.001. PMC 2822721. PMID 20152552.
  12. Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED (2003). "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V". American Journal of Human Genetics. 72 (5): 1293–9. doi:10.1086/375039. PMC 1180282. PMID 12690580.
  13. Sivakumar K, Kyriakides T, Puls I, Nicholson GA, Funalot B, Antonellis A, Sambuughin N, Christodoulou K, Beggs JL, Zamba-Papanicolaou E, Ionasescu V, Dalakas MC, Green ED, Fischbeck KH, Goldfarb LG (Oct 2005). "Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations". Brain. 128 (Pt 10): 2304–14. doi:10.1093/brain/awh590. PMID 16014653.
  14. Motley WW, Seburn KL, Nawaz MH, Miers KE, Cheng J, Antonellis A, Green ED, Talbot K, Yang XL, Fischbeck KH, Burgess RW (Dec 2011). "Charcot-Marie-Tooth-linked mutant GARS is toxic to peripheral neurons independent of wild-type GARS levels". PLOS Genetics. 7 (12): e1002399. doi:10.1371/journal.pgen.1002399. PMC 3228828. PMID 22144914.
  15. Seburn KL, Nangle LA, Cox GA, Schimmel P, Burgess RW (Sep 2006). "An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model". Neuron. 51 (6): 715–26. doi:10.1016/j.neuron.2006.08.027. PMID 16982418. S2CID 11035583.
  16. Achilli F, Bros-Facer V, Williams HP, Banks GT, AlQatari M, Chia R, Tucci V, Groves M, Nickols CD, Seburn KL, Kendall R, Cader MZ, Talbot K, van Minnen J, Burgess RW, Brandner S, Martin JE, Koltzenburg M, Greensmith L, Nolan PM, Fisher EM (Jul–Aug 2009). "An ENU-induced mutation in mouse glycyl-tRNA synthetase (GARS) causes peripheral sensory and motor phenotypes creating a model of Charcot-Marie-Tooth type 2D peripheral neuropathy". Disease Models & Mechanisms. 2 (7–8): 359–73. doi:10.1242/dmm.002527. PMC 2707104. PMID 19470612.
  17. Sleigh JN, Grice SJ, Burgess RW, Talbot K, Cader MZ (May 2014). "Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice". Human Molecular Genetics. 23 (10): 2639–50. doi:10.1093/hmg/ddt659. PMC 3990164. PMID 24368416.
  18. Spaulding EL, Sleigh JN, Morelli KH, Pinter MJ, Burgess RW, Seburn KL (2016). "Synaptic Deficits at Neuromuscular Junctions in Two Mouse Models of Charcot-Marie-Tooth Type 2d". The Journal of Neuroscience. 36 (11): 3254–67. doi:10.1523/JNEUROSCI.1762-15.2016. PMC 4792937. PMID 26985035.

Further reading
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