ID GARS_HUMAN Reviewed; 739 AA. AC P41250; B3KQA2; B4DIA0; Q969Y1; DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot. DT 30-NOV-2010, sequence version 3. DT 31-JUL-2019, entry version 203. DE RecName: Full=Glycine--tRNA ligase; DE EC=6.1.1.14 {ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:24898252, ECO:0000269|PubMed:28675565}; DE AltName: Full=Diadenosine tetraphosphate synthetase {ECO:0000305|PubMed:19710017}; DE Short=Ap4A synthetase {ECO:0000305|PubMed:19710017}; DE EC=2.7.7.- {ECO:0000269|PubMed:19710017}; DE AltName: Full=Glycyl-tRNA synthetase {ECO:0000303|PubMed:19710017}; DE Short=GlyRS {ECO:0000303|PubMed:19710017}; GN Name=GARS; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ALA-42. RX PubMed=7962006; RA Shiba K., Schimmel P., Motegi H., Noda T.; RT "Human glycyl-tRNA synthetase. Wide divergence of primary structure RT from bacterial counterpart and species-specific aminoacylation."; RL J. Biol. Chem. 269:30049-30055(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ALA-42. RX PubMed=7753621; DOI=10.1093/nar/23.8.1307; RA Williams J.H., Osvath S.R., Khong T.-F., Pearse M.J., Power D.A.; RT "Cloning, sequencing and bacterial expression of human glycine tRNA RT synthetase."; RL Nucleic Acids Res. 23:1307-1310(1995). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-42. RC TISSUE=Embryo, and Hippocampus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A., RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S., RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M., RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C., RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P., RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J., RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L., RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R., RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D., RA Waterston R.H., Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-42. RC TISSUE=Eye, and Muscle; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-739, AND VARIANT ALA-42. RX PubMed=7961834; RA Ge Q., Trieu E.P., Targoff I.N.; RT "Primary structure and functional expression of human glycyl-tRNA RT synthetase, an autoantigen in myositis."; RL J. Biol. Chem. 269:28790-28797(1994). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY. RC TISSUE=Lymphoblast; RX PubMed=14654843; DOI=10.1038/nature02166; RA Andersen J.S., Wilkinson C.J., Mayor T., Mortensen P., Nigg E.A., RA Mann M.; RT "Proteomic characterization of the human centrosome by protein RT correlation profiling."; RL Nature 426:570-574(2003). RN [8] RP SUBCELLULAR LOCATION, VARIANTS CMT2D GLY-125 AND ARG-294, RP CHARACTERIZATION OF VARIANTS CMT2D GLY-125 AND ARG-294, VARIANTS HMN5A RP PRO-183; ARG-472 AND ARG-580, AND CHARACTERIZATION OF VARIANTS HMN5A RP PRO-183; ARG-472 AND ARG-580. RX PubMed=17035524; DOI=10.1523/JNEUROSCI.1671-06.2006; RA Antonellis A., Lee-Lin S.Q., Wasterlain A., Leo P., Quezado M., RA Goldfarb L.G., Myung K., Burgess S., Fischbeck K.H., Green E.D.; RT "Functional analyses of glycyl-tRNA synthetase mutations suggest a key RT role for tRNA-charging enzymes in peripheral axons."; RL J. Neurosci. 26:10397-10406(2006). RN [9] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-204 AND LYS-501, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., RA Walther T.C., Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-35 AND THR-736, VARIANT RP [LARGE SCALE ANALYSIS] ALA-42, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [12] RP SUBCELLULAR LOCATION, VARIANTS CMT2D VAL-111; ASN-200; PHE-265; RP ARG-294; LEU-298; PHE-334; ARG-472; ASN-554; ARG-580 AND ALA-652, RP VARIANT LEU-635, CHARACTERIZATION OF VARIANTS CMT2D VAL-111; GLY-125; RP PRO-183; ASN-200; PHE-265; ARG-294; LEU-298; PHE-334; ARG-472; RP ASN-554; ARG-580 AND ALA-652, AND CHARACTERIZATION OF VARIANT LEU-635. RX PubMed=25168514; DOI=10.1002/humu.22681; RA Griffin L.B., Sakaguchi R., McGuigan D., Gonzalez M.A., Searby C., RA Zuchner S., Hou Y.M., Antonellis A.; RT "Impaired function is a common feature of neuropathy-associated RT glycyl-tRNA synthetase mutations."; RL Hum. Mutat. 35:1363-1371(2014). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., RA Ayoub D., Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [15] RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 55-739, FUNCTION, SUBUNIT, RP CHARACTERIZATION OF VARIANT LEU-635, CATALYTIC ACTIVITY, AND RP BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=17544401; DOI=10.1016/j.febslet.2007.05.046; RA Cader M.Z., Ren J., James P.A., Bird L.E., Talbot K., Stammers D.K.; RT "Crystal structure of human wildtype and S581L-mutant glycyl-tRNA RT synthetase, an enzyme underlying distal spinal muscular atrophy."; RL FEBS Lett. 581:2959-2964(2007). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 55-739, VARIANT ARG-580, AND RP SUBUNIT. RX PubMed=17545306; DOI=10.1073/pnas.0703908104; RA Xie W., Nangle L.A., Zhang W., Schimmel P., Yang X.-L.; RT "Long-range structural effects of a Charcot-Marie-Tooth disease- RT causing mutation in human glycyl-tRNA synthetase."; RL Proc. Natl. Acad. Sci. U.S.A. 104:9976-9981(2007). RN [17] {ECO:0000244|PDB:2ZT5, ECO:0000244|PDB:2ZT6, ECO:0000244|PDB:2ZT7, ECO:0000244|PDB:2ZT8, ECO:0000244|PDB:2ZXF} RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 55-739 IN COMPLEXES WITH RP ATP; AP4A; GLYCINE AND SUBSTRATE ANALOGS, FUNCTION, CATALYTIC RP ACTIVITY, ACTIVITY REGULATION, REACTION MECHANISM, AND SUBUNIT. RX PubMed=19710017; DOI=10.1074/jbc.M109.030692; RA Guo R.-T., Chong Y.E., Guo M., Yang X.-L.; RT "Crystal structures and biochemical analyses suggest a unique RT mechanism and role for human glycyl-tRNA synthetase in Ap4A RT homeostasis."; RL J. Biol. Chem. 284:28968-28976(2009). RN [18] {ECO:0000244|PDB:4KR2, ECO:0000244|PDB:4KR3} RP X-RAY CRYSTALLOGRAPHY (3.23 ANGSTROMS) OF 114-739 OF WILD-TYPE AND RP VARIANT GLY-125 IN COMPLEXES WITH TRNA(GLY); AMP; ATP ANALOG AND RP GLYCINE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, MUTAGENESIS OF RP ARG-121; ARG-337; ARG-602; TYR-658 AND GLN-729, AND CHARACTERIZATION RP OF VARIANT GLY-125. RX PubMed=24898252; DOI=10.1074/jbc.M114.557249; RA Qin X., Hao Z., Tian Q., Zhang Z., Zhou C., Xie W.; RT "Cocrystal structures of glycyl-tRNA synthetase in complex with tRNA RT suggest multiple conformational states in glycylation."; RL J. Biol. Chem. 289:20359-20369(2014). RN [19] {ECO:0000244|PDB:4KQE, ECO:0000244|PDB:4QEI} RP X-RAY CRYSTALLOGRAPHY (2.74 ANGSTROMS) OF 55-739 OF VARIANT GLY-125 RP AND DOUBLE MUTANT GLY-125/ARG-211 IN COMPLEX WITH TRNA(GLY) AND AMP, RP AND MUTAGENESIS OF CYS-211 AND 486-LEU--LYS-490. RX PubMed=26797133; DOI=10.1074/jbc.M115.679126; RA Deng X., Qin X., Chen L., Jia Q., Zhang Y., Zhang Z., Lei D., Ren G., RA Zhou Z., Wang Z., Li Q., Xie W.; RT "Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA RT Synthetase (hGlyRS) during Catalysis."; RL J. Biol. Chem. 291:5740-5752(2016). RN [20] {ECO:0000244|PDB:5E6M} RP X-RAY CRYSTALLOGRAPHY (2.93 ANGSTROMS) OF 55-739 IN COMPLEX WITH RP TRNA(GLY) AND GLYCYL-AMP. RX PubMed=27261259; DOI=10.1016/j.jmb.2016.05.018; RA Qin X., Deng X., Chen L., Xie W.; RT "Crystal Structure of the Wild-Type Human GlyRS Bound with tRNA(Gly) RT in a Productive Conformation."; RL J. Mol. Biol. 428:3603-3614(2016). RN [21] RP VARIANTS CMT2D GLY-125 AND ARG-294, VARIANTS HMN5A PRO-183 AND RP ARG-580, AND TISSUE SPECIFICITY. RX PubMed=12690580; DOI=10.1086/375039; RA Antonellis A., Ellsworth R.E., Sambuughin N., Puls I., Abel A., RA Lee-Lin S.Q., Jordanova A., Kremensky I., Christodoulou K., RA Middleton L.T., Sivakumar K., Ionasescu V., Funalot B., Vance J.M., RA Goldfarb L.G., Fischbeck K.H., Green E.D.; RT "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type RT 2D and distal spinal muscular atrophy type V."; RL Am. J. Hum. Genet. 72:1293-1299(2003). RN [22] RP VARIANT LEU-635, AND VARIANTS CMT2D PHE-334 AND ALA-652. RX PubMed=17101916; DOI=10.1212/01.wnl.0000242619.52335.bc; RA James P.A., Cader M.Z., Muntoni F., Childs A.M., Crow Y.J., Talbot K.; RT "Severe childhood SMA and axonal CMT due to anticodon binding domain RT mutations in the GARS gene."; RL Neurology 67:1710-1712(2006). RN [23] RP VARIANT CMT2D VAL-111. RX PubMed=17663003; DOI=10.1016/j.jns.2007.06.047; RA Rohkamm B., Reilly M.M., Lochmueller H., Schlotter-Weigel B., RA Barisic N., Schoels L., Nicholson G., Pareyson D., Laura M., RA Janecke A.R., Miltenberger-Miltenyi G., John E., Fischer C., Grill F., RA Wakeling W., Davis M., Pieber T.R., Auer-Grumbach M.; RT "Further evidence for genetic heterogeneity of distal HMN type V, CMT2 RT with predominant hand involvement and Silver syndrome."; RL J. Neurol. Sci. 263:100-106(2007). RN [24] RP VARIANT CMT2D LEU-298. RX PubMed=20169446; DOI=10.1007/s00415-010-5491-x; RA Hamaguchi A., Ishida C., Iwasa K., Abe A., Yamada M.; RT "Charcot-Marie-Tooth disease type 2D with a novel glycyl-tRNA RT synthetase gene (GARS) mutation."; RL J. Neurol. 257:1202-1204(2010). RN [25] RP VARIANTS HMN5A ASN-200 AND PHE-265. RX PubMed=23279345; DOI=10.1111/j.1529-8027.2012.00442.x; RA Lee H.J., Park J., Nakhro K., Park J.M., Hur Y.M., Choi B.O., RA Chung K.W.; RT "Two novel mutations of GARS in Korean families with distal hereditary RT motor neuropathy type V."; RL J. Peripher. Nerv. Syst. 17:418-421(2012). RN [26] RP VARIANT HMN5A ARG-472. RX PubMed=24627108; DOI=10.1007/s00415-014-7289-8; RA Schabhuettl M., Wieland T., Senderek J., Baets J., Timmerman V., RA De Jonghe P., Reilly M.M., Stieglbauer K., Laich E., Windhager R., RA Erwa W., Trajanoski S., Strom T.M., Auer-Grumbach M.; RT "Whole-exome sequencing in patients with inherited neuropathies: RT outcome and challenges."; RL J. Neurol. 261:970-982(2014). RN [27] RP VARIANT CMT2D PHE-334. RX PubMed=24604904; DOI=10.1136/jnnp-2013-306740; RA Klein C.J., Middha S., Duan X., Wu Y., Litchy W.J., Gu W., Dyck P.J., RA Gavrilova R.H., Smith D.I., Kocher J.P., Dyck P.J.; RT "Application of whole exome sequencing in undiagnosed inherited RT polyneuropathies."; RL J. Neurol. Neurosurg. Psych. 85:1265-1272(2014). RN [28] RP VARIANTS CMT2D TYR-200 AND ARG-292. RX PubMed=26244500; DOI=10.1371/journal.pone.0133423; RA Liao Y.C., Liu Y.T., Tsai P.C., Chang C.C., Huang Y.H., Soong B.W., RA Lee Y.C.; RT "Two novel de novo gars mutations cause early-onset axonal Charcot- RT Marie-tooth disease."; RL PLoS ONE 10:E0133423-E0133423(2015). RN [29] RP CHARACTERIZATION OF VARIANTS CMT2D GLY-125 AND ARG-294, AND RP CHARACTERIZATION OF VARIANT HMN5A PRO-183. RX PubMed=26503042; DOI=10.1038/nature15510; RA He W., Bai G., Zhou H., Wei N., White N.M., Lauer J., Liu H., Shi Y., RA Dumitru C.D., Lettieri K., Shubayev V., Jordanova A., RA Guergueltcheva V., Griffin P.R., Burgess R.W., Pfaff S.L., Yang X.L.; RT "CMT2D neuropathy is linked to the neomorphic binding activity of RT glycyl-tRNA synthetase."; RL Nature 526:710-714(2015). RN [30] RP ERRATUM. RX PubMed=26789244; DOI=10.1038/nature16499; RA He W., Bai G., Zhou H., Wei N., White N.M., Lauer J., Liu H., Shi Y., RA Dan Dumitru C., Lettieri K., Shubayev V., Jordanova A., RA Guergueltcheva V., Griffin P.R., Burgess R.W., Pfaff S.L., Yang X.L.; RT "Corrigendum: CMT2D neuropathy is linked to the neomorphic binding RT activity of glycyl-tRNA synthetase."; RL Nature 532:402-402(2016). RN [31] RP VARIANT GLN-310, CHARACTERIZATION OF VARIANT GLN-310, CATALYTIC RP ACTIVITY, FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=28675565; DOI=10.1002/humu.23287; RA Oprescu S.N., Chepa-Lotrea X., Takase R., Golas G., Markello T.C., RA Adams D.R., Toro C., Gropman A.L., Hou Y.M., Malicdan M.C.V., RA Gahl W.A., Tifft C.J., Antonellis A.; RT "Compound heterozygosity for loss-of-function GARS variants results in RT a multisystem developmental syndrome that includes severe growth RT retardation."; RL Hum. Mutat. 38:1412-1420(2017). RN [32] RP VARIANTS ILE-268 AND CYS-412. RX PubMed=28594869; DOI=10.1371/journal.pone.0178125; RA Nafisinia M., Riley L.G., Gold W.A., Bhattacharya K., Broderick C.R., RA Thorburn D.R., Simons C., Christodoulou J.; RT "Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) RT cause mitochondrial respiratory chain dysfunction."; RL PLoS ONE 12:E0178125-E0178125(2017). CC -!- FUNCTION: Catalyzes the ATP-dependent ligation of glycine to the CC 3'-end of its cognate tRNA, via the formation of an aminoacyl- CC adenylate intermediate (Gly-AMP) (PubMed:17544401, CC PubMed:28675565, PubMed:24898252). Also produces diadenosine CC tetraphosphate (Ap4A), a universal pleiotropic signaling molecule CC needed for cell regulation pathways, by direct condensation of 2 CC ATPs. Thereby, may play a special role in Ap4A homeostasis CC (PubMed:19710017). {ECO:0000269|PubMed:17544401, CC ECO:0000269|PubMed:19710017, ECO:0000269|PubMed:24898252, CC ECO:0000269|PubMed:28675565}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + glycine + tRNA(Gly) = AMP + diphosphate + glycyl- CC tRNA(Gly); Xref=Rhea:RHEA:16013, Rhea:RHEA-COMP:9664, Rhea:RHEA- CC COMP:9683, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:57305, ChEBI:CHEBI:78442, ChEBI:CHEBI:78522, CC ChEBI:CHEBI:456215; EC=6.1.1.14; CC Evidence={ECO:0000269|PubMed:17544401, CC ECO:0000269|PubMed:24898252, ECO:0000269|PubMed:28675565}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16014; CC Evidence={ECO:0000305|PubMed:24898252}; CC -!- CATALYTIC ACTIVITY: CC Reaction=2 ATP + H(+) = diphosphate + P(1),P(4)-bis(5'-adenosyl) CC tetraphosphate; Xref=Rhea:RHEA:34935, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58141; CC Evidence={ECO:0000269|PubMed:19710017}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:34936; CC Evidence={ECO:0000305|PubMed:19710017}; CC -!- ACTIVITY REGULATION: Ap4A synthesis is inhibited by tRNA, via the CC disruption of the second ATP-binding site by direct blocking CC and/or by tRNA-induced conformational change. CC {ECO:0000269|PubMed:19710017}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.3 uM for tRNA(Gly(GCC)) {ECO:0000269|PubMed:17544401}; CC KM=15 uM for glycine {ECO:0000269|PubMed:17544401}; CC KM=0.74 uM for tRNA(Gly) {ECO:0000269|PubMed:28675565}; CC Note=kcat is 0.049 sec(-1) for aminoacylation of tRNA(Gly). CC {ECO:0000269|PubMed:28675565}; CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:17544401, CC ECO:0000269|PubMed:17545306, ECO:0000305|PubMed:19710017, CC ECO:0000305|PubMed:24898252}. CC -!- INTERACTION: CC Self; NbExp=4; IntAct=EBI-724143, EBI-724143; CC Q9CZD3:Gars (xeno); NbExp=2; IntAct=EBI-724143, EBI-8321941; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17035524}. CC Cell projection, axon {ECO:0000269|PubMed:17035524, CC ECO:0000269|PubMed:25168514}. Secreted CC {ECO:0000250|UniProtKB:Q9CZD3}. Secreted, exosome CC {ECO:0000250|UniProtKB:Q9CZD3}. Note=Secreted by motor neuron, CC possibly through the exosome pathway (By similarity). In CC transfected COS7 cells, not detected in mitochondria, nor in Golgi CC apparatus (PubMed:17035524). {ECO:0000250|UniProtKB:Q9CZD3, CC ECO:0000269|PubMed:17035524}. CC -!- TISSUE SPECIFICITY: Widely expressed, including in brain and CC spinal cord. {ECO:0000269|PubMed:12690580}. CC -!- DISEASE: Charcot-Marie-Tooth disease 2D (CMT2D) [MIM:601472]: A CC dominant axonal form of Charcot-Marie-Tooth disease, a disorder of CC the peripheral nervous system, characterized by progressive CC weakness and atrophy, initially of the peroneal muscles and later CC of the distal muscles of the arms. Charcot-Marie-Tooth disease is CC classified in two main groups on the basis of electrophysiologic CC properties and histopathology: primary peripheral demyelinating CC neuropathies (designated CMT1 when they are dominantly inherited) CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of CC the CMT2 group are characterized by signs of axonal degeneration CC in the absence of obvious myelin alterations, normal or slightly CC reduced nerve conduction velocities, and progressive distal muscle CC weakness and atrophy. {ECO:0000269|PubMed:12690580, CC ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:17101916, CC ECO:0000269|PubMed:17663003, ECO:0000269|PubMed:20169446, CC ECO:0000269|PubMed:24604904, ECO:0000269|PubMed:25168514, CC ECO:0000269|PubMed:26244500, ECO:0000269|PubMed:26503042}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. Contrary to the wild-type protein, CC CMT2D variants Gly-125 and Arg-294 strongly interact with NRP1. CC This interaction may compete out VEGFA binding and inhibits VEGFA- CC NRP1 signling which is essential for motor neuron survival, as CC suggested by experiments done in a mouse model. CC {ECO:0000269|PubMed:26503042}. CC -!- DISEASE: Neuronopathy, distal hereditary motor, 5A (HMN5A) CC [MIM:600794]: A disorder characterized by distal muscular atrophy CC mainly affecting the upper extremities, in contrast to other CC distal motor neuronopathies. These constitute a heterogeneous CC group of neuromuscular diseases caused by selective degeneration CC of motor neurons in the anterior horn of the spinal cord, without CC sensory deficit in the posterior horn. The overall clinical CC picture consists of a classical distal muscular atrophy syndrome CC in the legs without clinical sensory loss. The disease starts with CC weakness and wasting of distal muscles of the anterior tibial and CC peroneal compartments of the legs. Later on, weakness and atrophy CC may expand to the proximal muscles of the lower limbs and/or to CC the distal upper limbs. {ECO:0000269|PubMed:12690580, CC ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:23279345, CC ECO:0000269|PubMed:24627108, ECO:0000269|PubMed:26503042}. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. Contrary to the wild-type protein, CC HMN5A variant Pro-183 strongly interacts with NRP1. This CC interaction may compete out VEGFA binding and inhibits VEGFA-NRP1 CC signling which is essential for motor neuron survival, as CC suggested by experiments done in a mouse model. CC {ECO:0000269|PubMed:26503042}. CC -!- MISCELLANEOUS: Human GlyRS uses direct ATP condensation to CC synthesize Ap4A, a unique amino acid-independent mechanism, in CC contrast to the classical amino acid-dependent mechanism for CC synthesis of Ap4A by a tRNA synthetase, that involves the CC generation of an enzyme-bound aminoacyl-AMP which is then attacked CC by ATP to form Ap4A. {ECO:0000269|PubMed:19710017}. CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase CC family. {ECO:0000305}. CC -!- CAUTION: According to a report, variant Leu-635 induces reduced CC activity (PubMed:17544401). According to another report, it does CC not affect function (PubMed:25168514). CC {ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:25168514}. CC -!- SEQUENCE CAUTION: CC Sequence=AAA57001.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305}; CC Sequence=AAA86443.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Inherited peripheral neuropathies mutation db; CC URL="http://www.molgen.ua.ac.be/CMTMutations/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D30658; BAA06338.1; -; mRNA. DR EMBL; U09510; AAA86443.1; ALT_INIT; mRNA. DR EMBL; AK074524; BAG51964.1; -; mRNA. DR EMBL; AK295490; BAG58412.1; -; mRNA. DR EMBL; AC005154; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC006969; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC004976; AAC71652.1; -; Genomic_DNA. DR EMBL; BC007722; AAH07722.1; -; mRNA. DR EMBL; BC007755; AAH07755.1; -; mRNA. DR EMBL; U09587; AAA57001.1; ALT_INIT; mRNA. DR CCDS; CCDS43564.1; -. DR PIR; A55314; A55314. DR RefSeq; NP_001303701.1; NM_001316772.1. DR RefSeq; NP_002038.2; NM_002047.3. DR PDB; 2PME; X-ray; 2.90 A; A=55-739. DR PDB; 2PMF; X-ray; 2.85 A; A=55-739. DR PDB; 2Q5H; X-ray; 3.00 A; A=55-739. DR PDB; 2Q5I; X-ray; 2.80 A; A=55-739. DR PDB; 2ZT5; X-ray; 2.50 A; A=55-739. DR PDB; 2ZT6; X-ray; 3.08 A; A=55-739. DR PDB; 2ZT7; X-ray; 2.70 A; A=55-739. DR PDB; 2ZT8; X-ray; 3.35 A; A=55-739. DR PDB; 2ZXF; X-ray; 3.40 A; A=55-739. DR PDB; 4KQE; X-ray; 2.74 A; A=55-739. DR PDB; 4KR2; X-ray; 3.29 A; A=114-739. DR PDB; 4KR3; X-ray; 3.24 A; A=114-739. DR PDB; 4QEI; X-ray; 2.88 A; A=118-739. DR PDB; 5E6M; X-ray; 2.93 A; A/B=55-739. DR PDBsum; 2PME; -. DR PDBsum; 2PMF; -. DR PDBsum; 2Q5H; -. DR PDBsum; 2Q5I; -. DR PDBsum; 2ZT5; -. DR PDBsum; 2ZT6; -. DR PDBsum; 2ZT7; -. DR PDBsum; 2ZT8; -. DR PDBsum; 2ZXF; -. DR PDBsum; 4KQE; -. DR PDBsum; 4KR2; -. DR PDBsum; 4KR3; -. DR PDBsum; 4QEI; -. DR PDBsum; 5E6M; -. DR SMR; P41250; -. DR BioGrid; 108887; 112. DR DIP; DIP-50471N; -. DR IntAct; P41250; 24. DR MINT; P41250; -. DR STRING; 9606.ENSP00000373918; -. DR ChEMBL; CHEMBL4105815; -. DR DrugBank; DB00145; Glycine. DR MoonProt; P41250; -. DR iPTMnet; P41250; -. DR PhosphoSitePlus; P41250; -. DR SwissPalm; P41250; -. DR BioMuta; GARS; -. DR DMDM; 313104283; -. DR EPD; P41250; -. DR jPOST; P41250; -. DR MaxQB; P41250; -. DR PaxDb; P41250; -. DR PeptideAtlas; P41250; -. DR PRIDE; P41250; -. DR ProteomicsDB; 55453; -. DR DNASU; 2617; -. DR Ensembl; ENST00000389266; ENSP00000373918; ENSG00000106105. DR GeneID; 2617; -. DR KEGG; hsa:2617; -. DR UCSC; uc003tbm.4; human. DR CTD; 2617; -. DR DisGeNET; 2617; -. DR GeneCards; GARS; -. DR GeneReviews; GARS; -. DR HGNC; HGNC:4162; GARS. DR HPA; HPA017896; -. DR HPA; HPA019097; -. DR MalaCards; GARS; -. DR MIM; 600287; gene. DR MIM; 600794; phenotype. DR MIM; 601472; phenotype. DR neXtProt; NX_P41250; -. DR OpenTargets; ENSG00000106105; -. DR Orphanet; 99938; Autosomal dominant Charcot-Marie-Tooth disease type 2D. DR Orphanet; 139536; Distal hereditary motor neuropathy type 5. DR PharmGKB; PA28575; -. DR eggNOG; KOG2298; Eukaryota. DR eggNOG; COG0423; LUCA. DR GeneTree; ENSGT00940000153759; -. DR HOGENOM; HOG000242015; -. DR InParanoid; P41250; -. DR KO; K01880; -. DR OMA; EPSYGID; -. DR OrthoDB; 1183820at2759; -. DR PhylomeDB; P41250; -. DR TreeFam; TF343504; -. DR BRENDA; 6.1.1.14; 2681. DR Reactome; R-HSA-379716; Cytosolic tRNA aminoacylation. DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation. DR SABIO-RK; P41250; -. DR ChiTaRS; GARS; human. DR EvolutionaryTrace; P41250; -. DR GeneWiki; Glycine%E2%80%94tRNA_ligase; -. DR GenomeRNAi; 2617; -. DR PMAP-CutDB; P41250; -. DR PRO; PR:P41250; -. DR Proteomes; UP000005640; Chromosome 7. DR Bgee; ENSG00000106105; Expressed in 237 organ(s), highest expression level in secondary oocyte. DR ExpressionAtlas; P41250; baseline and differential. DR Genevisible; P41250; HS. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; ISS:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central. DR GO; GO:0030141; C:secretory granule; IEA:Ensembl. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004081; F:bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity; IDA:UniProtKB. DR GO; GO:0004820; F:glycine-tRNA ligase activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046983; F:protein dimerization activity; IDA:UniProtKB. DR GO; GO:0016740; F:transferase activity; IEA:UniProtKB-KW. DR GO; GO:0015966; P:diadenosine tetraphosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0006426; P:glycyl-tRNA aminoacylation; IBA:GO_Central. DR GO; GO:0070150; P:mitochondrial glycyl-tRNA aminoacylation; IBA:GO_Central. DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; IMP:UniProtKB. DR CDD; cd00774; GlyRS-like_core; 1. DR Gene3D; 3.40.50.800; -; 1. DR InterPro; IPR002314; aa-tRNA-synt_IIb. DR InterPro; IPR006195; aa-tRNA-synth_II. DR InterPro; IPR004154; Anticodon-bd. DR InterPro; IPR036621; Anticodon-bd_dom_sf. DR InterPro; IPR027031; Gly-tRNA_synthase/POLG2. DR InterPro; IPR033731; GlyRS-like_core. DR InterPro; IPR009068; S15_NS1_RNA-bd. DR InterPro; IPR002315; tRNA-synt_gly. DR InterPro; IPR000738; WHEP-TRS_dom. DR PANTHER; PTHR10745; PTHR10745; 1. DR Pfam; PF03129; HGTP_anticodon; 1. DR Pfam; PF00587; tRNA-synt_2b; 1. DR Pfam; PF00458; WHEP-TRS; 1. DR PRINTS; PR01043; TRNASYNTHGLY. DR SMART; SM00991; WHEP-TRS; 1. DR SUPFAM; SSF47060; SSF47060; 1. DR TIGRFAMs; TIGR00389; glyS_dimeric; 1. DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1. DR PROSITE; PS00762; WHEP_TRS_1; 1. DR PROSITE; PS51185; WHEP_TRS_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding; KW Cell projection; Charcot-Marie-Tooth disease; Complete proteome; KW Cytoplasm; Disease mutation; Hydrolase; Ligase; Neurodegeneration; KW Neuropathy; Nucleotide-binding; Phosphoprotein; Protein biosynthesis; KW Reference proteome; Secreted; Transferase. FT CHAIN 1 739 Glycine--tRNA ligase. FT /FTId=PRO_0000072998. FT DOMAIN 63 119 WHEP-TRS. {ECO:0000255|PROSITE- FT ProRule:PRU00531}. FT NP_BIND 331 333 ATP. {ECO:0000244|PDB:2ZT7, FT ECO:0000269|PubMed:19710017, FT ECO:0000305|PubMed:24898252, FT ECO:0000305|PubMed:27261259}. FT NP_BIND 342 343 ATP. {ECO:0000244|PDB:2ZT7, FT ECO:0000269|PubMed:19710017}. FT NP_BIND 457 458 ATP. {ECO:0000244|PDB:2ZT7, FT ECO:0000269|PubMed:19710017, FT ECO:0000305|PubMed:24898252, FT ECO:0000305|PubMed:27261259}. FT REGION 576 578 Glycine binding. {ECO:0000244|PDB:2ZT7, FT ECO:0000244|PDB:4KR3, FT ECO:0000269|PubMed:19710017, FT ECO:0000269|PubMed:24898252}. FT BINDING 299 299 Glycine. {ECO:0000244|PDB:2ZT7, FT ECO:0000244|PDB:4KR3, FT ECO:0000269|PubMed:19710017, FT ECO:0000269|PubMed:24898252, FT ECO:0000305|PubMed:27261259}. FT BINDING 350 350 Glycine. {ECO:0000244|PDB:2ZT7, FT ECO:0000244|PDB:4KR3, FT ECO:0000269|PubMed:19710017, FT ECO:0000269|PubMed:24898252, FT ECO:0000305|PubMed:27261259}. FT BINDING 583 583 ATP. {ECO:0000244|PDB:2ZT7, FT ECO:0000269|PubMed:19710017}. FT MOD_RES 35 35 Phosphoserine. FT {ECO:0000244|PubMed:23186163}. FT MOD_RES 204 204 N6-acetyllysine. FT {ECO:0000244|PubMed:19608861}. FT MOD_RES 453 453 Phosphotyrosine. FT {ECO:0000250|UniProtKB:Q9CZD3}. FT MOD_RES 501 501 N6-acetyllysine. FT {ECO:0000244|PubMed:19608861}. FT MOD_RES 700 700 Phosphoserine. FT {ECO:0000250|UniProtKB:Q9CZD3}. FT MOD_RES 736 736 Phosphothreonine. FT {ECO:0000244|PubMed:23186163}. FT VARIANT 42 42 P -> A (in dbSNP:rs1049402). FT {ECO:0000244|PubMed:23186163, FT ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:7753621, FT ECO:0000269|PubMed:7961834, FT ECO:0000269|PubMed:7962006}. FT /FTId=VAR_054865. FT VARIANT 111 111 A -> V (in CMT2D; shows a reduction in FT aminoacylation activity; FT dbSNP:rs370531212). FT {ECO:0000269|PubMed:17663003, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073187. FT VARIANT 125 125 E -> G (in CMT2D; phenotype overlapping FT with DSMA-V; complements the defect of FT the wild-type gene in yeast; contrary to FT the wild-type protein, strongly binds to FT NRP1 and competes with VEGFA for NRP1- FT binding; displays slightly elevated FT aminoacylation activity over wild-type; FT dbSNP:rs137852645). FT {ECO:0000269|PubMed:12690580, FT ECO:0000269|PubMed:17035524, FT ECO:0000269|PubMed:24898252, FT ECO:0000269|PubMed:25168514, FT ECO:0000269|PubMed:26503042}. FT /FTId=VAR_018718. FT VARIANT 183 183 L -> P (in HMN5A; does not complement the FT defect of the wild-type gene in yeast; FT contrary to the wild-type protein, FT strongly interacts with NRP1; FT dbSNP:rs137852644). FT {ECO:0000269|PubMed:12690580, FT ECO:0000269|PubMed:17035524, FT ECO:0000269|PubMed:25168514, FT ECO:0000269|PubMed:26503042}. FT /FTId=VAR_018719. FT VARIANT 200 200 D -> N (in CMT2D and HMN5A; shows a large FT reduction in aminoacylation activity). FT {ECO:0000269|PubMed:23279345, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073188. FT VARIANT 200 200 D -> Y (in CMT2D). FT {ECO:0000269|PubMed:26244500}. FT /FTId=VAR_074016. FT VARIANT 265 265 S -> F (in CMT2D and HMN5A; shows a large FT reduction in aminoacylation activity; FT demonstrates a change in the subcellular FT location pattern; does not associate with FT granules; dbSNP:rs1554337974). FT {ECO:0000269|PubMed:23279345, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073189. FT VARIANT 268 268 T -> I (found in a patient with mild left FT ventricular posterior wall hypertrophy, FT exercise intolerance and lactic acidosis; FT unknown pathological significance; FT dbSNP:rs2230310). FT {ECO:0000269|PubMed:28594869}. FT /FTId=VAR_054866. FT VARIANT 292 292 M -> R (in CMT2D). FT {ECO:0000269|PubMed:26244500}. FT /FTId=VAR_074017. FT VARIANT 294 294 G -> R (in CMT2D; shows a large reduction FT in aminoacylation activity; does not FT impair transcription or translation or FT protein stability; contrary to the wild- FT type protein, strongly interacts with FT NRP1; dbSNP:rs137852643). FT {ECO:0000269|PubMed:12690580, FT ECO:0000269|PubMed:17035524, FT ECO:0000269|PubMed:25168514, FT ECO:0000269|PubMed:26503042}. FT /FTId=VAR_018720. FT VARIANT 298 298 P -> L (in CMT2D; shows a large reduction FT in aminoacylation activity; demonstrates FT a change in subcellular location pattern; FT does not associate with granules; FT dbSNP:rs137852648). FT {ECO:0000269|PubMed:20169446, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073190. FT VARIANT 310 310 R -> Q (probable disease-associated FT mutation found in a patient with growth FT retardation, microcephaly, thinning of FT the corpus callosum, decreased white FT matter and brain stem involvement, as FT well as large calvaria, cerebellar vermis FT atrophy, dysmorphic features, prominent FT epicanthal folds, hypotelorism, high- FT arched palate, delayed motor milestones, FT apnea and sparse thin scalp hair; reduces FT to less than 1% aminoacylation activity; FT dbSNP:rs1135401748). FT {ECO:0000269|PubMed:28675565}. FT /FTId=VAR_079827. FT VARIANT 334 334 I -> F (in CMT2D; shows a large reduction FT in aminoacylation activity; demonstrates FT a change in subcellular location pattern; FT does not associate with granules; unknown FT pathological significance; FT dbSNP:rs1554338260). FT {ECO:0000269|PubMed:17101916, FT ECO:0000269|PubMed:24604904, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073191. FT VARIANT 388 388 R -> Q (in dbSNP:rs17159287). FT /FTId=VAR_054867. FT VARIANT 412 412 R -> C (found in a patient with mild left FT ventricular posterior wall hypertrophy, FT exercise intolerance and lactic acidosis; FT unknown pathological significance; FT dbSNP:rs770924455). FT {ECO:0000269|PubMed:28594869}. FT /FTId=VAR_079828. FT VARIANT 472 472 H -> R (in HMN5A; shows a large reduction FT in aminoacylation activity; does not FT complement the defect of the wild-type FT gene in yeast; dbSNP:rs1060502838). FT {ECO:0000269|PubMed:17035524, FT ECO:0000269|PubMed:24627108, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073192. FT VARIANT 554 554 D -> N (in CMT2D; demonstrates no change FT in subcellular location pattern; FT dbSNP:rs137852647). FT {ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073193. FT VARIANT 580 580 G -> R (in HMN5A; higher dimerization FT stability; loss of activity; shows a FT large reduction in aminoacylation FT activity; dbSNP:rs137852646). FT {ECO:0000269|PubMed:12690580, FT ECO:0000269|PubMed:17035524, FT ECO:0000269|PubMed:17545306, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_018721. FT VARIANT 598 598 G -> A (in HMN5A; unknown pathological FT significance; dbSNP:rs766280100). FT {ECO:0000269|PubMed:17101916}. FT /FTId=VAR_079829. FT VARIANT 635 635 S -> L (polymorphism; has no effect on FT subcellular localization; results in FT reduced activity; dbSNP:rs201358272). FT {ECO:0000269|PubMed:17101916, FT ECO:0000269|PubMed:17544401, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073194. FT VARIANT 652 652 G -> A (in CMT2D; shows a large reduction FT in aminoacylation activity; demonstrates FT a change in subcellular location pattern; FT does not associate with granules). FT {ECO:0000269|PubMed:17101916, FT ECO:0000269|PubMed:25168514}. FT /FTId=VAR_073195. FT MUTAGEN 121 121 R->A: Decrease in catalytic activity by FT about 10-fold. FT {ECO:0000269|PubMed:24898252}. FT MUTAGEN 211 211 C->R: Displays 62% of wild-type catalytic FT activity. Displays 20% of wild-type FT catalytic activity; when associated with FT G-125. {ECO:0000269|PubMed:26797133}. FT MUTAGEN 337 337 R->A: Decrease in catalytic activity by FT more than 10-fold. FT {ECO:0000269|PubMed:24898252}. FT MUTAGEN 486 490 Missing: Loss of catalytic activity. FT {ECO:0000269|PubMed:26797133}. FT MUTAGEN 602 602 R->A: Decrease in catalytic activity by FT more than 10-fold. FT {ECO:0000269|PubMed:24898252}. FT MUTAGEN 658 658 Y->F: Decrease in catalytic activity by FT more than 10-fold. FT {ECO:0000269|PubMed:24898252}. FT MUTAGEN 729 729 Q->A,N: Decrease in catalytic activity by FT about 10-fold. FT {ECO:0000269|PubMed:24898252}. FT CONFLICT 9 18 Missing (in Ref. 3; BAG58412). FT {ECO:0000305}. FT CONFLICT 205 205 D -> G (in Ref. 3; BAG51964). FT {ECO:0000305}. FT CONFLICT 530 530 M -> I (in Ref. 2; AAA86443). FT {ECO:0000305}. FT CONFLICT 634 634 L -> S (in Ref. 3; BAG51964). FT {ECO:0000305}. FT TURN 62 64 {ECO:0000244|PDB:5E6M}. FT HELIX 65 80 {ECO:0000244|PDB:5E6M}. FT TURN 81 83 {ECO:0000244|PDB:5E6M}. FT HELIX 95 112 {ECO:0000244|PDB:5E6M}. FT HELIX 121 130 {ECO:0000244|PDB:2ZT5}. FT STRAND 133 136 {ECO:0000244|PDB:2ZT5}. FT HELIX 139 141 {ECO:0000244|PDB:2ZT5}. FT STRAND 148 150 {ECO:0000244|PDB:2ZT5}. FT HELIX 152 168 {ECO:0000244|PDB:2ZT5}. FT HELIX 170 173 {ECO:0000244|PDB:2ZT5}. FT STRAND 182 185 {ECO:0000244|PDB:2ZT5}. FT HELIX 186 191 {ECO:0000244|PDB:2ZT5}. FT HELIX 194 197 {ECO:0000244|PDB:2ZT5}. FT STRAND 199 208 {ECO:0000244|PDB:2ZT5}. FT STRAND 211 213 {ECO:0000244|PDB:2ZT5}. FT HELIX 214 227 {ECO:0000244|PDB:2ZT5}. FT STRAND 229 231 {ECO:0000244|PDB:2Q5I}. FT HELIX 233 243 {ECO:0000244|PDB:2ZT5}. FT TURN 244 248 {ECO:0000244|PDB:2ZT5}. FT HELIX 251 260 {ECO:0000244|PDB:2ZT5}. FT STRAND 266 268 {ECO:0000244|PDB:2ZT5}. FT STRAND 276 279 {ECO:0000244|PDB:2ZT5}. FT STRAND 283 285 {ECO:0000244|PDB:2ZT5}. FT STRAND 287 296 {ECO:0000244|PDB:2ZT5}. FT STRAND 298 300 {ECO:0000244|PDB:2ZXF}. FT HELIX 301 305 {ECO:0000244|PDB:2ZT5}. FT HELIX 308 314 {ECO:0000244|PDB:2ZT5}. FT TURN 315 317 {ECO:0000244|PDB:2ZT5}. FT STRAND 321 330 {ECO:0000244|PDB:2ZT5}. FT HELIX 339 341 {ECO:0000244|PDB:2ZT5}. FT STRAND 344 355 {ECO:0000244|PDB:2ZT5}. FT HELIX 357 359 {ECO:0000244|PDB:4KQE}. FT HELIX 365 367 {ECO:0000244|PDB:2ZT5}. FT TURN 368 370 {ECO:0000244|PDB:2ZT5}. FT STRAND 372 376 {ECO:0000244|PDB:2ZT5}. FT HELIX 378 382 {ECO:0000244|PDB:2ZT5}. FT STRAND 388 391 {ECO:0000244|PDB:2ZT5}. FT HELIX 392 397 {ECO:0000244|PDB:2ZT5}. FT STRAND 400 402 {ECO:0000244|PDB:2PME}. FT HELIX 404 420 {ECO:0000244|PDB:2ZT5}. FT HELIX 424 426 {ECO:0000244|PDB:2ZT5}. FT STRAND 427 431 {ECO:0000244|PDB:2ZT5}. FT HELIX 434 436 {ECO:0000244|PDB:2ZT5}. FT STRAND 442 451 {ECO:0000244|PDB:2ZT5}. FT STRAND 454 462 {ECO:0000244|PDB:2ZT5}. FT HELIX 467 476 {ECO:0000244|PDB:2ZT5}. FT STRAND 482 484 {ECO:0000244|PDB:2ZT5}. FT HELIX 501 507 {ECO:0000244|PDB:4KQE}. FT HELIX 512 519 {ECO:0000244|PDB:4KQE}. FT HELIX 524 535 {ECO:0000244|PDB:4KQE}. FT STRAND 541 544 {ECO:0000244|PDB:4KQE}. FT STRAND 547 550 {ECO:0000244|PDB:4KQE}. FT STRAND 552 554 {ECO:0000244|PDB:4KQE}. FT STRAND 562 564 {ECO:0000244|PDB:2PMF}. FT TURN 565 567 {ECO:0000244|PDB:2PMF}. FT STRAND 568 570 {ECO:0000244|PDB:2ZT5}. FT STRAND 573 580 {ECO:0000244|PDB:2ZT5}. FT HELIX 581 592 {ECO:0000244|PDB:2ZT5}. FT STRAND 593 595 {ECO:0000244|PDB:2ZT5}. FT STRAND 597 600 {ECO:0000244|PDB:4KQE}. FT STRAND 603 605 {ECO:0000244|PDB:2ZT5}. FT TURN 609 611 {ECO:0000244|PDB:2ZT5}. FT STRAND 615 621 {ECO:0000244|PDB:2ZT5}. FT TURN 625 627 {ECO:0000244|PDB:2ZT5}. FT HELIX 628 640 {ECO:0000244|PDB:2ZT5}. FT STRAND 645 647 {ECO:0000244|PDB:2ZT5}. FT STRAND 650 652 {ECO:0000244|PDB:5E6M}. FT HELIX 654 663 {ECO:0000244|PDB:2ZT5}. FT STRAND 668 672 {ECO:0000244|PDB:2ZT5}. FT HELIX 674 677 {ECO:0000244|PDB:2ZT5}. FT STRAND 679 681 {ECO:0000244|PDB:2ZT5}. FT STRAND 683 688 {ECO:0000244|PDB:2ZT5}. FT TURN 689 691 {ECO:0000244|PDB:2ZT5}. FT STRAND 694 698 {ECO:0000244|PDB:2ZT5}. FT TURN 699 701 {ECO:0000244|PDB:2ZT5}. FT HELIX 702 710 {ECO:0000244|PDB:2ZT5}. FT STRAND 712 714 {ECO:0000244|PDB:4KR3}. FT HELIX 716 722 {ECO:0000244|PDB:2ZT5}. SQ SEQUENCE 739 AA; 83166 MW; E4C001CEBF985C59 CRC64; MPSPRPVLLR GARAALLLLL PPRLLARPSL LLRRSLSAAS CPPISLPAAA SRSSMDGAGA EEVLAPLRLA VRQQGDLVRK LKEDKAPQVD VDKAVAELKA RKRVLEAKEL ALQPKDDIVD RAKMEDTLKR RFFYDQAFAI YGGVSGLYDF GPVGCALKNN IIQTWRQHFI QEEQILEIDC TMLTPEPVLK TSGHVDKFAD FMVKDVKNGE CFRADHLLKA HLQKLMSDKK CSVEKKSEME SVLAQLDNYG QQELADLFVN YNVKSPITGN DLSPPVSFNL MFKTFIGPGG NMPGYLRPET AQGIFLNFKR LLEFNQGKLP FAAAQIGNSF RNEISPRSGL IRVREFTMAE IEHFVDPSEK DHPKFQNVAD LHLYLYSAKA QVSGQSARKM RLGDAVEQGV INNTVLGYFI GRIYLYLTKV GISPDKLRFR QHMENEMAHY ACDCWDAESK TSYGWIEIVG CADRSCYDLS CHARATKVPL VAEKPLKEPK TVNVVQFEPS KGAIGKAYKK DAKLVMEYLA ICDECYITEM EMLLNEKGEF TIETEGKTFQ LTKDMINVKR FQKTLYVEEV VPNVIEPSFG LGRIMYTVFE HTFHVREGDE QRTFFSFPAV VAPFKCSVLP LSQNQEFMPF VKELSEALTR HGVSHKVDDS SGSIGRRYAR TDEIGVAFGV TIDFDTVNKT PHTATLRDRD SMRQIRAEIS ELPSIVQDLA NGNITWADVE ARYPLFEGQE TGKKETIEE //