GARS_HUMAN
ID GARS_HUMAN Reviewed; 739 AA.
AC P41250; A0A090N8G0; B3KQA2; B4DIA0; Q969Y1;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 30-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 220.
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};
DE AltName: Full=Glycyl-tRNA synthetase 1 {ECO:0000312|HGNC:HGNC:4162};
DE Flags: Precursor;
GN Name=GARS1 {ECO:0000312|HGNC:HGNC:4162}; Synonyms=GARS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALA-42.
RX PubMed=7962006; DOI=10.1016/s0021-9258(18)43986-5;
RA Shiba K., Schimmel P., Motegi H., Noda T.;
RT "Human glycyl-tRNA synthetase. Wide divergence of primary structure from
RT bacterial counterpart and species-specific aminoacylation.";
RL J. Biol. Chem. 269:30049-30055(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), 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] (ISOFORM 1), 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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., 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., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [5] {ECO:0000312|EMBL:EAL24449.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-739 (ISOFORM 1), AND VARIANT ALA-42.
RX PubMed=7961834; DOI=10.1016/s0021-9258(19)61975-7;
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 [8]
RP INVOLVEMENT IN CMT2D, VARIANTS CMT2D GLY-125 AND ARG-294, VARIANTS HMN5A
RP PRO-183 AND 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., Middleton L.T.,
RA Sivakumar K., Ionasescu V., Funalot B., Vance J.M., Goldfarb L.G.,
RA Fischbeck K.H., Green E.D.;
RT "Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D
RT and distal spinal muscular atrophy type V.";
RL Am. J. Hum. Genet. 72:1293-1299(2003).
RN [9]
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., Mann M.;
RT "Proteomic characterization of the human centrosome by protein correlation
RT profiling.";
RL Nature 426:570-574(2003).
RN [10]
RP SUBCELLULAR LOCATION, VARIANTS CMT2D GLY-125 AND ARG-294, CHARACTERIZATION
RP OF VARIANTS CMT2D GLY-125 AND ARG-294, VARIANTS HMN5A PRO-183; ARG-472 AND
RP ARG-580, AND CHARACTERIZATION OF VARIANTS HMN5A PRO-183; ARG-472 AND
RP 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 role
RT for tRNA-charging enzymes in peripheral axons.";
RL J. Neurosci. 26:10397-10406(2006).
RN [11]
RP SUBCELLULAR LOCATION (ISOFORMS 1 AND 2).
RX PubMed=17529987; DOI=10.1038/nn1910;
RA Chihara T., Luginbuhl D., Luo L.;
RT "Cytoplasmic and mitochondrial protein translation in axonal and dendritic
RT terminal arborization.";
RL Nat. Neurosci. 10:828-837(2007).
RN [12]
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., Walther T.C.,
RA 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 [13]
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., Buerckstuemmer T.,
RA 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 [14]
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 [15]
RP SUBCELLULAR LOCATION (ISOFORM 2), VARIANTS CMT2D VAL-111; ASN-200; PHE-265;
RP ARG-294; LEU-298; PHE-334; ARG-472; ASN-554; ARG-580 AND ALA-652, VARIANT
RP LEU-635, CHARACTERIZATION OF VARIANTS CMT2D VAL-111; GLY-125; PRO-183;
RP ASN-200; PHE-265; ARG-294; LEU-298; PHE-334; ARG-472; ASN-554; ARG-580 AND
RP 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 glycyl-tRNA
RT synthetase mutations.";
RL Hum. Mutat. 35:1363-1371(2014).
RN [16]
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., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
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., Ayoub D.,
RA 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 [18]
RP ALTERNATIVE INITIATION, SUBCELLULAR LOCATION (ISOFORMS 1 AND 2), AND TISSUE
RP SPECIFICITY (ISOFORMS 1 AND 2).
RX PubMed=26327585; DOI=10.1080/15476286.2015.1086866;
RA Alexandrova J., Paulus C., Rudinger-Thirion J., Jossinet F., Frugier M.;
RT "Elaborate uORF/IRES features control expression and localization of human
RT glycyl-tRNA synthetase.";
RL RNA Biol. 12:1301-1313(2015).
RN [19]
RP INVOLVEMENT IN SMAJI, VARIANTS SMAJI ASN-334 AND ARG-652, AND
RP CHARACTERIZATION OF VARIANT SMAJI ASN-334.
RX PubMed=32181591; DOI=10.1002/ajmg.a.61544;
RA Markovitz R., Ghosh R., Kuo M.E., Hong W., Lim J., Bernes S., Manberg S.,
RA Crosby K., Tanpaiboon P., Bharucha-Goebel D., Bonnemann C., Mohila C.A.,
RA Mizerik E., Woodbury S., Bi W., Lotze T., Antonellis A., Xiao R.,
RA Potocki L.;
RT "GARS-related disease in infantile spinal muscular atrophy: Implications
RT for diagnosis and treatment.";
RL Am. J. Med. Genet. A 182:1167-1176(2020).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF ISOFORM 2, 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 [21]
RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF ISOFORM 2, 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-causing
RT mutation in human glycyl-tRNA synthetase.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:9976-9981(2007).
RN [22] {ECO:0007744|PDB:2ZT5, ECO:0007744|PDB:2ZT6, ECO:0007744|PDB:2ZT7, ECO:0007744|PDB:2ZT8, ECO:0007744|PDB:2ZXF}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF ISOFORM 2 IN COMPLEXES WITH ATP;
RP AP4A; GLYCINE AND SUBSTRATE ANALOGS, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP 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 mechanism and
RT role for human glycyl-tRNA synthetase in Ap4A homeostasis.";
RL J. Biol. Chem. 284:28968-28976(2009).
RN [23] {ECO:0007744|PDB:4KR2, ECO:0007744|PDB:4KR3}
RP X-RAY CRYSTALLOGRAPHY (3.23 ANGSTROMS) OF 114-739 OF WILD-TYPE AND VARIANT
RP GLY-125 IN COMPLEXES WITH TRNA(GLY); AMP; ATP ANALOG AND GLYCINE, FUNCTION,
RP CATALYTIC ACTIVITY, SUBUNIT, MUTAGENESIS OF ARG-121; ARG-337; ARG-602;
RP TYR-658 AND GLN-729, AND CHARACTERIZATION 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 [24] {ECO:0007744|PDB:4KQE, ECO:0007744|PDB:4QEI}
RP X-RAY CRYSTALLOGRAPHY (2.74 ANGSTROMS) OF ISOFORM 2 WITH VARIANT GLY-125
RP AND DOUBLE MUTANT GLY-125/ARG-211 IN COMPLEX WITH TRNA(GLY) AND AMP, AND
RP 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 [25] {ECO:0007744|PDB:5E6M}
RP X-RAY CRYSTALLOGRAPHY (2.93 ANGSTROMS) OF ISOFORM 2 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) in a
RT Productive Conformation.";
RL J. Mol. Biol. 428:3603-3614(2016).
RN [26]
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 [27]
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., Barisic N.,
RA Schoels L., Nicholson G., Pareyson D., Laura M., Janecke A.R.,
RA Miltenberger-Miltenyi G., John E., Fischer C., Grill F., Wakeling W.,
RA Davis M., Pieber T.R., Auer-Grumbach M.;
RT "Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with
RT predominant hand involvement and Silver syndrome.";
RL J. Neurol. Sci. 263:100-106(2007).
RN [28]
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 synthetase
RT gene (GARS) mutation.";
RL J. Neurol. 257:1202-1204(2010).
RN [29]
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., 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 [30]
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., Erwa W.,
RA Trajanoski S., Strom T.M., Auer-Grumbach M.;
RT "Whole-exome sequencing in patients with inherited neuropathies: outcome
RT and challenges.";
RL J. Neurol. 261:970-982(2014).
RN [31]
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 [32]
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-Marie-
RT tooth disease.";
RL PLoS ONE 10:E0133423-E0133423(2015).
RN [33]
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., Guergueltcheva V.,
RA Griffin P.R., Burgess R.W., Pfaff S.L., Yang X.L.;
RT "CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-
RT tRNA synthetase.";
RL Nature 526:710-714(2015).
RN [34]
RP ERRATUM OF PUBMED:26503042.
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., Guergueltcheva V.,
RA Griffin P.R., Burgess R.W., Pfaff S.L., Yang X.L.;
RT "Corrigendum: CMT2D neuropathy is linked to the neomorphic binding activity
RT of glycyl-tRNA synthetase.";
RL Nature 532:402-402(2016).
RN [35]
RP VARIANT GLN-310, CHARACTERIZATION OF VARIANT GLN-310, CATALYTIC ACTIVITY,
RP 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., Gahl W.A.,
RA Tifft C.J., Antonellis A.;
RT "Compound heterozygosity for loss-of-function GARS variants results in a
RT multisystem developmental syndrome that includes severe growth
RT retardation.";
RL Hum. Mutat. 38:1412-1420(2017).
RN [36]
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) cause
RT mitochondrial respiratory chain dysfunction.";
RL PLoS ONE 12:E0178125-E0178125(2017).
RN [37]
RP VARIANT CMT2D TYR-265.
RX PubMed=31173493; DOI=10.1002/mgg3.782;
RG H3Africa Consortium;
RA Yalcouye A., Diallo S.H., Coulibaly T., Cisse L., Diallo S., Samassekou O.,
RA Diarra S., Coulibaly D., Keita M., Guinto C.O., Fischbeck K., Landoure G.;
RT "A novel mutation in the GARS gene in a Malian family with Charcot-Marie-
RT Tooth disease.";
RL Mol. Genet. Genomic Med. 7:e00782-e00782(2019).
CC -!- FUNCTION: Catalyzes the ATP-dependent ligation of glycine to the 3'-end
CC of its cognate tRNA, via the formation of an aminoacyl-adenylate
CC intermediate (Gly-AMP) (PubMed:17544401, PubMed:28675565,
CC PubMed:24898252). Also produces diadenosine tetraphosphate (Ap4A), a
CC universal pleiotropic signaling molecule needed for cell regulation
CC pathways, by direct condensation of 2 ATPs. Thereby, may play a special
CC role in Ap4A homeostasis (PubMed:19710017).
CC {ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:19710017,
CC ECO:0000269|PubMed:24898252, 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, ChEBI:CHEBI:57305,
CC ChEBI:CHEBI:78442, ChEBI:CHEBI:78522, ChEBI:CHEBI:456215;
CC EC=6.1.1.14; 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 and/or by
CC tRNA-induced conformational change. {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 P41250; Q16520: BATF; NbExp=3; IntAct=EBI-724143, EBI-749503;
CC P41250; Q9UNS2: COPS3; NbExp=3; IntAct=EBI-724143, EBI-350590;
CC P41250; P41250: GARS1; NbExp=4; IntAct=EBI-724143, EBI-724143;
CC P41250; Q99612: KLF6; NbExp=3; IntAct=EBI-724143, EBI-714994;
CC P41250; Q9BR81: PCDHGC3; NbExp=3; IntAct=EBI-724143, EBI-22012354;
CC P41250; Q8WXH5: SOCS4; NbExp=3; IntAct=EBI-724143, EBI-3942425;
CC P41250; Q99932-2: SPAG8; NbExp=3; IntAct=EBI-724143, EBI-11959123;
CC P41250; Q9CZD3: Gars1; Xeno; NbExp=2; IntAct=EBI-724143, EBI-8321941;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:17035524}. Cell
CC projection, axon {ECO:0000269|PubMed:17035524}. Secreted
CC {ECO:0000250|UniProtKB:Q9CZD3}. Secreted, extracellular exosome
CC {ECO:0000250|UniProtKB:Q9CZD3}. Note=In transfected COS7 cells, not
CC detected in mitochondria, nor in Golgi apparatus (PubMed:17035524).
CC Secreted by motor neuron, possibly through the exosome pathway (By
CC similarity). {ECO:0000250|UniProtKB:Q9CZD3,
CC ECO:0000269|PubMed:17035524}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Mitochondrion
CC {ECO:0000269|PubMed:17529987, ECO:0000269|PubMed:26327585}. Cytoplasm
CC {ECO:0000269|PubMed:26327585}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000269|PubMed:17529987, ECO:0000269|PubMed:26327585}. Cell
CC projection, axon {ECO:0000269|PubMed:25168514}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=2;
CC Name=1 {ECO:0000305};
CC IsoId=P41250-1; Sequence=Displayed;
CC Name=2 {ECO:0000305};
CC IsoId=P41250-2; Sequence=VSP_060970;
CC -!- TISSUE SPECIFICITY: Widely expressed, including in brain and spinal
CC cord. {ECO:0000269|PubMed:12690580}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in brain, spinal cord,
CC muscle, heart and spleen. {ECO:0000269|PubMed:26327585}.
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in brain, spinal cord,
CC muscle, heart, spleen and liver. {ECO:0000269|PubMed:26327585}.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2D (CMT2D) [MIM:601472]: A
CC dominant axonal form of Charcot-Marie-Tooth disease, a disorder of the
CC peripheral nervous system, characterized by progressive weakness and
CC atrophy, initially of the peroneal muscles and later of the distal
CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two
CC main groups on the basis of electrophysiologic properties and
CC histopathology: primary peripheral demyelinating neuropathies
CC (designated CMT1 when they are dominantly inherited) and primary
CC peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group
CC are characterized by signs of axonal degeneration in the absence of
CC obvious myelin alterations, normal or slightly reduced nerve conduction
CC velocities, and progressive distal muscle weakness and atrophy.
CC {ECO:0000269|PubMed:12690580, ECO:0000269|PubMed:17035524,
CC ECO:0000269|PubMed:17101916, ECO:0000269|PubMed:17663003,
CC ECO:0000269|PubMed:20169446, ECO:0000269|PubMed:24604904,
CC ECO:0000269|PubMed:25168514, ECO:0000269|PubMed:26244500,
CC ECO:0000269|PubMed:26503042, ECO:0000269|PubMed:31173493}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
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 distal
CC motor neuronopathies. These constitute a heterogeneous group of
CC neuromuscular diseases caused by selective degeneration of motor
CC neurons in the anterior horn of the spinal cord, without sensory
CC deficit in the posterior horn. The overall clinical picture consists of
CC a classical distal muscular atrophy syndrome in the legs without
CC clinical sensory loss. The disease starts with weakness and wasting of
CC distal muscles of the anterior tibial and peroneal compartments of the
CC legs. Later on, weakness and atrophy may expand to the proximal muscles
CC of the lower limbs and/or to the distal upper limbs.
CC {ECO:0000269|PubMed:12690580, ECO:0000269|PubMed:17035524,
CC ECO:0000269|PubMed:23279345, ECO:0000269|PubMed:24627108,
CC ECO:0000269|PubMed:26503042}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Spinal muscular atrophy, infantile, James type (SMAJI)
CC [MIM:619042]: An autosomal dominant form of spinal muscular atrophy, a
CC group of neuromuscular disorders characterized by degeneration of the
CC anterior horn cells of the spinal cord, leading to symmetrical muscle
CC weakness and atrophy. SMAJI is a severe disease characterized by
CC hypotonia manifesting in the first weeks or months of life, delayed
CC motor development, motor regression, and muscle weakness and atrophy
CC primarily affecting distal muscles. Additional variable features
CC include feeding difficulties, poor overall growth, foot deformities,
CC kyphosis, hyperlordosis, scoliosis, vocal cord dysfunction, and
CC respiratory insufficiency. {ECO:0000269|PubMed:32181591}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: Human GlyRS uses direct ATP condensation to synthesize
CC Ap4A, a unique amino acid-independent mechanism, in contrast to the
CC classical amino acid-dependent mechanism for synthesis of Ap4A by a
CC tRNA synthetase, that involves the generation of an enzyme-bound
CC aminoacyl-AMP which is then attacked by ATP to form Ap4A.
CC {ECO:0000269|PubMed:19710017}.
CC -!- MISCELLANEOUS: [Isoform 2]: The isoform 2 translation is regulated by
CC an Internal Ribosome Entry Site (IRES) and an upstream Open Reading
CC Frame. Both are important in hindering the synthesis of the
CC mitochondrial GARS and target the translation of the cytosolic enzyme
CC to ER-bound ribosomes. {ECO:0000305|PubMed:26327585}.
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase family.
CC {ECO:0000305}.
CC -!- CAUTION: According to a report, variant Leu-635 induces reduced
CC activity (PubMed:17544401). According to another report, it does not
CC affect function (PubMed:25168514). {ECO:0000269|PubMed:17544401,
CC ECO:0000269|PubMed:25168514}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA57001.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAA86443.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Inherited peripheral neuropathies mutation db;
CC URL="https://uantwerpen.vib.be/CMTMutations";
CC ---------------------------------------------------------------------------
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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; AACC02000087; EAL24449.1; -; 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; -. [P41250-1]
DR PIR; A55314; A55314.
DR RefSeq; NP_001303701.1; NM_001316772.1. [P41250-2]
DR RefSeq; NP_002038.2; NM_002047.3. [P41250-1]
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 AlphaFoldDB; P41250; -.
DR SMR; P41250; -.
DR BioGRID; 108887; 178.
DR DIP; DIP-50471N; -.
DR IntAct; P41250; 40.
DR MINT; P41250; -.
DR STRING; 9606.ENSP00000373918; -.
DR ChEMBL; CHEMBL4105815; -.
DR DrugBank; DB00145; Glycine.
DR MoonProt; P41250; -.
DR GlyGen; P41250; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P41250; -.
DR MetOSite; P41250; -.
DR PhosphoSitePlus; P41250; -.
DR SwissPalm; P41250; -.
DR BioMuta; GARS; -.
DR DMDM; 313104283; -.
DR EPD; P41250; -.
DR jPOST; P41250; -.
DR MassIVE; P41250; -.
DR MaxQB; P41250; -.
DR PaxDb; P41250; -.
DR PeptideAtlas; P41250; -.
DR PRIDE; P41250; -.
DR ProteomicsDB; 55453; -.
DR ABCD; P41250; 3 sequenced antibodies.
DR Antibodypedia; 6744; 377 antibodies from 32 providers.
DR DNASU; 2617; -.
DR Ensembl; ENST00000389266.8; ENSP00000373918.3; ENSG00000106105.15. [P41250-1]
DR GeneID; 2617; -.
DR KEGG; hsa:2617; -.
DR MANE-Select; ENST00000389266.8; ENSP00000373918.3; NM_002047.4; NP_002038.2.
DR UCSC; uc003tbm.4; human. [P41250-1]
DR CTD; 2617; -.
DR DisGeNET; 2617; -.
DR GeneCards; GARS1; -.
DR GeneReviews; GARS1; -.
DR HGNC; HGNC:4162; GARS1.
DR HPA; ENSG00000106105; Low tissue specificity.
DR MalaCards; GARS1; -.
DR MIM; 600287; gene.
DR MIM; 600794; phenotype.
DR MIM; 601472; phenotype.
DR MIM; 619042; 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 VEuPathDB; HostDB:ENSG00000106105; -.
DR eggNOG; KOG2298; Eukaryota.
DR GeneTree; ENSGT00940000153759; -.
DR HOGENOM; CLU_015515_1_0_1; -.
DR InParanoid; P41250; -.
DR OMA; EPSYGID; -.
DR OrthoDB; 1183820at2759; -.
DR PhylomeDB; P41250; -.
DR TreeFam; TF343504; -.
DR BRENDA; 6.1.1.14; 2681.
DR PathwayCommons; P41250; -.
DR Reactome; R-HSA-379716; Cytosolic tRNA aminoacylation.
DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation.
DR SABIO-RK; P41250; -.
DR SignaLink; P41250; -.
DR BioGRID-ORCS; 2617; 781 hits in 1098 CRISPR screens.
DR ChiTaRS; GARS; human.
DR EvolutionaryTrace; P41250; -.
DR GeneWiki; Glycine%E2%80%94tRNA_ligase; -.
DR GenomeRNAi; 2617; -.
DR Pharos; P41250; Tchem.
DR PRO; PR:P41250; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; P41250; protein.
DR Bgee; ENSG00000106105; Expressed in secondary oocyte and 215 other tissues.
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; 3.30.930.10; -; 1.
DR Gene3D; 3.40.50.800; -; 1.
DR InterPro; IPR002314; aa-tRNA-synt_IIb.
DR InterPro; IPR006195; aa-tRNA-synth_II.
DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL.
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 SUPFAM; SSF55681; SSF55681; 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; Alternative initiation;
KW Aminoacyl-tRNA synthetase; ATP-binding; Cell projection;
KW Charcot-Marie-Tooth disease; Cytoplasm; Disease variant; Hydrolase; Ligase;
KW Mitochondrion; Neurodegeneration; Neuropathy; Nucleotide-binding;
KW Phosphoprotein; Protein biosynthesis; Reference proteome; Secreted;
KW Transferase; Transit peptide.
FT TRANSIT 1..36
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 37..739
FT /note="Glycine--tRNA ligase"
FT /evidence="ECO:0000255"
FT /id="PRO_0000072998"
FT DOMAIN 63..119
FT /note="WHEP-TRS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00531"
FT BINDING 299
FT /ligand="glycine"
FT /ligand_id="ChEBI:CHEBI:57305"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0000269|PubMed:24898252, ECO:0000305|PubMed:27261259,
FT ECO:0007744|PDB:2ZT7, ECO:0007744|PDB:4KR3"
FT BINDING 331..333
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0000305|PubMed:24898252, ECO:0000305|PubMed:27261259,
FT ECO:0007744|PDB:2ZT7"
FT BINDING 342..343
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0007744|PDB:2ZT7"
FT BINDING 350
FT /ligand="glycine"
FT /ligand_id="ChEBI:CHEBI:57305"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0000269|PubMed:24898252, ECO:0000305|PubMed:27261259,
FT ECO:0007744|PDB:2ZT7, ECO:0007744|PDB:4KR3"
FT BINDING 457..458
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0000305|PubMed:24898252, ECO:0000305|PubMed:27261259,
FT ECO:0007744|PDB:2ZT7"
FT BINDING 576..578
FT /ligand="glycine"
FT /ligand_id="ChEBI:CHEBI:57305"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0000269|PubMed:24898252, ECO:0007744|PDB:2ZT7,
FT ECO:0007744|PDB:4KR3"
FT BINDING 583
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:19710017,
FT ECO:0007744|PDB:2ZT7"
FT MOD_RES 35
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 204
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 453
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q9CZD3"
FT MOD_RES 501
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 700
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9CZD3"
FT MOD_RES 736
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..54
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000312|EMBL:EAL24449.1"
FT /id="VSP_060970"
FT VARIANT 42
FT /note="P -> A (in dbSNP:rs1049402)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:7753621,
FT ECO:0000269|PubMed:7961834, ECO:0000269|PubMed:7962006,
FT ECO:0007744|PubMed:23186163"
FT /id="VAR_054865"
FT VARIANT 111
FT /note="A -> V (in CMT2D; shows a reduction in
FT aminoacylation activity; dbSNP:rs370531212)"
FT /evidence="ECO:0000269|PubMed:17663003,
FT ECO:0000269|PubMed:25168514"
FT /id="VAR_073187"
FT VARIANT 125
FT /note="E -> G (in CMT2D; phenotype overlapping with HMN5A;
FT complements the defect of the wild-type gene in yeast;
FT contrary to the wild-type protein, strongly binds to NRP1
FT and competes with VEGFA for NRP1-binding; displays slightly
FT elevated aminoacylation activity over wild-type;
FT dbSNP:rs137852645)"
FT /evidence="ECO:0000269|PubMed:12690580,
FT ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:24898252,
FT ECO:0000269|PubMed:25168514, ECO:0000269|PubMed:26503042"
FT /id="VAR_018718"
FT VARIANT 183
FT /note="L -> P (in HMN5A; does not complement the defect of
FT the wild-type gene in yeast; contrary to the wild-type
FT protein, strongly interacts with NRP1; dbSNP:rs137852644)"
FT /evidence="ECO:0000269|PubMed:12690580,
FT ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:25168514,
FT ECO:0000269|PubMed:26503042"
FT /id="VAR_018719"
FT VARIANT 200
FT /note="D -> N (in CMT2D and HMN5A; shows a large reduction
FT in aminoacylation activity; dbSNP:rs1554337369)"
FT /evidence="ECO:0000269|PubMed:23279345,
FT ECO:0000269|PubMed:25168514"
FT /id="VAR_073188"
FT VARIANT 200
FT /note="D -> Y (in CMT2D)"
FT /evidence="ECO:0000269|PubMed:26244500"
FT /id="VAR_074016"
FT VARIANT 265
FT /note="S -> F (in CMT2D and HMN5A; shows a large reduction
FT in aminoacylation activity; demonstrates a change in the
FT subcellular location pattern; does not associate with
FT granules; dbSNP:rs1554337974)"
FT /evidence="ECO:0000269|PubMed:23279345,
FT ECO:0000269|PubMed:25168514"
FT /id="VAR_073189"
FT VARIANT 265
FT /note="S -> Y (in CMT2D; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:31173493"
FT /id="VAR_085141"
FT VARIANT 268
FT /note="T -> I (found in a patient with mild left
FT ventricular posterior wall hypertrophy, exercise
FT intolerance and lactic acidosis; unknown pathological
FT significance; dbSNP:rs2230310)"
FT /evidence="ECO:0000269|PubMed:28594869"
FT /id="VAR_054866"
FT VARIANT 292
FT /note="M -> R (in CMT2D; dbSNP:rs1064795123)"
FT /evidence="ECO:0000269|PubMed:26244500"
FT /id="VAR_074017"
FT VARIANT 294
FT /note="G -> R (in CMT2D; shows a large reduction in
FT aminoacylation activity; does not impair transcription or
FT translation or protein stability; contrary to the wild-type
FT protein, strongly interacts with NRP1; dbSNP:rs137852643)"
FT /evidence="ECO:0000269|PubMed:12690580,
FT ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:25168514,
FT ECO:0000269|PubMed:26503042"
FT /id="VAR_018720"
FT VARIANT 298
FT /note="P -> L (in CMT2D; shows a large reduction in
FT aminoacylation activity; demonstrates a change in
FT subcellular location pattern; does not associate with
FT granules; dbSNP:rs137852648)"
FT /evidence="ECO:0000269|PubMed:20169446,
FT ECO:0000269|PubMed:25168514"
FT /id="VAR_073190"
FT VARIANT 310
FT /note="R -> Q (probable disease-associated variant found in
FT a patient with growth retardation, microcephaly, thinning
FT of the corpus callosum, decreased white matter and brain
FT stem involvement, as well as large calvaria, cerebellar
FT vermis atrophy, dysmorphic features, prominent epicanthal
FT folds, hypotelorism, high-arched palate, delayed motor
FT milestones, apnea and sparse thin scalp hair; reduces to
FT less than 1% aminoacylation activity; dbSNP:rs1135401748)"
FT /evidence="ECO:0000269|PubMed:28675565"
FT /id="VAR_079827"
FT VARIANT 334
FT /note="I -> F (in CMT2D; shows a large reduction in
FT aminoacylation activity; demonstrates a change in
FT subcellular location pattern; does not associate with
FT granules; unknown pathological significance;
FT dbSNP:rs1554338260)"
FT /evidence="ECO:0000269|PubMed:17101916,
FT ECO:0000269|PubMed:24604904, ECO:0000269|PubMed:25168514"
FT /id="VAR_073191"
FT VARIANT 334
FT /note="I -> N (in SMAJI; loss of function; based on yeast
FT complementation assay; dbSNP:rs1554338262)"
FT /evidence="ECO:0000269|PubMed:32181591"
FT /id="VAR_085142"
FT VARIANT 388
FT /note="R -> Q (in dbSNP:rs17159287)"
FT /id="VAR_054867"
FT VARIANT 412
FT /note="R -> C (found in a patient with mild left
FT ventricular posterior wall hypertrophy, exercise
FT intolerance and lactic acidosis; unknown pathological
FT significance; dbSNP:rs770924455)"
FT /evidence="ECO:0000269|PubMed:28594869"
FT /id="VAR_079828"
FT VARIANT 472
FT /note="H -> R (in HMN5A; shows a large reduction in
FT aminoacylation activity; does not complement the defect of
FT the wild-type gene in yeast; dbSNP:rs1060502838)"
FT /evidence="ECO:0000269|PubMed:17035524,
FT ECO:0000269|PubMed:24627108, ECO:0000269|PubMed:25168514"
FT /id="VAR_073192"
FT VARIANT 554
FT /note="D -> N (in CMT2D; demonstrates no change in
FT subcellular location pattern; dbSNP:rs137852647)"
FT /evidence="ECO:0000269|PubMed:25168514"
FT /id="VAR_073193"
FT VARIANT 580
FT /note="G -> R (in HMN5A; higher dimerization stability;
FT loss of activity; shows a large reduction in aminoacylation
FT activity; dbSNP:rs137852646)"
FT /evidence="ECO:0000269|PubMed:12690580,
FT ECO:0000269|PubMed:17035524, ECO:0000269|PubMed:17545306,
FT ECO:0000269|PubMed:25168514"
FT /id="VAR_018721"
FT VARIANT 598
FT /note="G -> A (in HMN5A; unknown pathological significance;
FT dbSNP:rs766280100)"
FT /evidence="ECO:0000269|PubMed:17101916"
FT /id="VAR_079829"
FT VARIANT 635
FT /note="S -> L (has no effect on subcellular localization;
FT results in reduced activity; dbSNP:rs201358272)"
FT /evidence="ECO:0000269|PubMed:17101916,
FT ECO:0000269|PubMed:17544401, ECO:0000269|PubMed:25168514"
FT /id="VAR_073194"
FT VARIANT 652
FT /note="G -> A (in CMT2D; shows a large reduction in
FT aminoacylation activity; demonstrates a change in
FT subcellular location pattern; does not associate with
FT granules; dbSNP:rs747080824)"
FT /evidence="ECO:0000269|PubMed:17101916,
FT ECO:0000269|PubMed:25168514"
FT /id="VAR_073195"
FT VARIANT 652
FT /note="G -> R (in SMAJI)"
FT /evidence="ECO:0000269|PubMed:32181591"
FT /id="VAR_085143"
FT MUTAGEN 121
FT /note="R->A: Decrease in catalytic activity by about 10-
FT fold."
FT /evidence="ECO:0000269|PubMed:24898252"
FT MUTAGEN 211
FT /note="C->R: Displays 62% of wild-type catalytic activity.
FT Displays 20% of wild-type catalytic activity; when
FT associated with G-125."
FT /evidence="ECO:0000269|PubMed:26797133"
FT MUTAGEN 337
FT /note="R->A: Decrease in catalytic activity by more than
FT 10-fold."
FT /evidence="ECO:0000269|PubMed:24898252"
FT MUTAGEN 486..490
FT /note="Missing: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:26797133"
FT MUTAGEN 602
FT /note="R->A: Decrease in catalytic activity by more than
FT 10-fold."
FT /evidence="ECO:0000269|PubMed:24898252"
FT MUTAGEN 658
FT /note="Y->F: Decrease in catalytic activity by more than
FT 10-fold."
FT /evidence="ECO:0000269|PubMed:24898252"
FT MUTAGEN 729
FT /note="Q->A,N: Decrease in catalytic activity by about 10-
FT fold."
FT /evidence="ECO:0000269|PubMed:24898252"
FT CONFLICT 9..18
FT /note="Missing (in Ref. 3; BAG58412)"
FT /evidence="ECO:0000305"
FT CONFLICT 205
FT /note="D -> G (in Ref. 3; BAG51964)"
FT /evidence="ECO:0000305"
FT CONFLICT 530
FT /note="M -> I (in Ref. 2; AAA86443)"
FT /evidence="ECO:0000305"
FT CONFLICT 634
FT /note="L -> S (in Ref. 3; BAG51964)"
FT /evidence="ECO:0000305"
FT TURN 62..64
FT /evidence="ECO:0007829|PDB:5E6M"
FT HELIX 65..80
FT /evidence="ECO:0007829|PDB:5E6M"
FT TURN 81..83
FT /evidence="ECO:0007829|PDB:5E6M"
FT HELIX 95..112
FT /evidence="ECO:0007829|PDB:5E6M"
FT HELIX 121..130
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 139..141
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 148..150
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 152..168
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 170..173
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 182..185
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 186..191
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 194..197
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 199..208
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 211..213
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 214..227
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 229..231
FT /evidence="ECO:0007829|PDB:2Q5I"
FT HELIX 233..243
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 244..248
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 251..260
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 266..268
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 276..279
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 287..296
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 298..300
FT /evidence="ECO:0007829|PDB:2ZXF"
FT HELIX 301..305
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 308..314
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 315..317
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 321..330
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 339..341
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 344..355
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 357..359
FT /evidence="ECO:0007829|PDB:4KQE"
FT HELIX 365..367
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 368..370
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 372..376
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 378..382
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 388..391
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 392..397
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 400..402
FT /evidence="ECO:0007829|PDB:2PME"
FT HELIX 404..420
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 424..426
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 427..431
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 434..436
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 442..451
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 454..462
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 467..476
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 482..484
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 501..507
FT /evidence="ECO:0007829|PDB:4KQE"
FT HELIX 512..519
FT /evidence="ECO:0007829|PDB:4KQE"
FT HELIX 524..535
FT /evidence="ECO:0007829|PDB:4KQE"
FT STRAND 541..544
FT /evidence="ECO:0007829|PDB:4KQE"
FT STRAND 547..550
FT /evidence="ECO:0007829|PDB:4KQE"
FT STRAND 552..554
FT /evidence="ECO:0007829|PDB:4KQE"
FT STRAND 562..564
FT /evidence="ECO:0007829|PDB:2PMF"
FT TURN 565..567
FT /evidence="ECO:0007829|PDB:2PMF"
FT STRAND 568..570
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 573..580
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 581..592
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 593..595
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 597..600
FT /evidence="ECO:0007829|PDB:4KQE"
FT STRAND 603..605
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 609..611
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 615..621
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 625..627
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 628..640
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 645..647
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 650..652
FT /evidence="ECO:0007829|PDB:5E6M"
FT HELIX 654..663
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 668..672
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 674..677
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 679..681
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 683..688
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 689..691
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 694..698
FT /evidence="ECO:0007829|PDB:2ZT5"
FT TURN 699..701
FT /evidence="ECO:0007829|PDB:2ZT5"
FT HELIX 702..710
FT /evidence="ECO:0007829|PDB:2ZT5"
FT STRAND 712..714
FT /evidence="ECO:0007829|PDB:4KR3"
FT HELIX 716..722
FT /evidence="ECO:0007829|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
