ID SYK_HUMAN Reviewed; 597 AA. AC Q15046; A8MSK1; D3DUK4; O14946; Q96J25; Q9HB23; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 16-APR-2002, sequence version 3. DT 27-MAR-2024, entry version 213. DE RecName: Full=Lysine--tRNA ligase; DE EC=2.7.7.- {ECO:0000269|PubMed:19524539, ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:5338216}; DE EC=6.1.1.6 {ECO:0000269|PubMed:18029264, ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:9278442}; DE AltName: Full=Lysyl-tRNA synthetase; DE Short=LysRS; GN Name=KARS1 {ECO:0000312|HGNC:HGNC:6215}; Synonyms=KARS, KIAA0070; 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 CYTOPLASMIC), FUNCTION, AND CATALYTIC RP ACTIVITY. RC TISSUE=Brain; RX PubMed=9278442; DOI=10.1074/jbc.272.36.22809; RA Shiba K., Stello T., Motegi H., Noda T., Musier-Forsyth K., Schimmel P.; RT "Human lysyl-tRNA synthetase accepts nucleotide 73 variants and rescues RT Escherichia coli double-defective mutant."; RL J. Biol. Chem. 272:22809-22816(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM MITOCHONDRIAL), SUBCELLULAR LOCATION, RP AND VARIANT SER-595. RX PubMed=10952987; DOI=10.1074/jbc.m006265200; RA Tolkunova E., Park H., Xia J., King M.P., Davidson E.; RT "The human lysyl-tRNA synthetase gene encodes both the cytoplasmic and RT mitochondrial enzymes by means of an unusual alternative splicing of the RT primary transcript."; RL J. Biol. Chem. 275:35063-35069(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CYTOPLASMIC), AND VARIANT RP SER-595. RC TISSUE=Bone marrow; RX PubMed=7584044; DOI=10.1093/dnares/1.5.223; RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S., Seki N., RA Kawarabayasi Y., Ishikawa K., Tabata S.; RT "Prediction of the coding sequences of unidentified human genes. II. The RT coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of RT cDNA clones from human cell line KG-1."; RL DNA Res. 1:223-229(1994). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM CYTOPLASMIC). RC TISSUE=Placenta; 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 PROTEIN SEQUENCE OF 2-10; 112-127; 142-148; 231-241; 306-314 AND 486-492, RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND IDENTIFICATION RP BY MASS SPECTROMETRY (ISOFORM CYTOPLASMIC). RC TISSUE=Hepatoma; RA Bienvenut W.V., Boldt K., von Kriegsheim A.F., Kolch W.; RL Submitted (JUL-2007) to UniProtKB. RN [8] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=5338216; DOI=10.1016/0006-291x(66)90415-3; RA Zamecnik P.C., Stephenson M.L., Janeway C.M., Randerath K.; RT "Enzymatic synthesis of diadenosine tetraphosphate and diadenosine RT triphosphate with a purified lysyl-tRNA synthetase."; RL Biochem. Biophys. Res. Commun. 24:91-97(1966). RN [9] RP INTERACTION WITH AIMP2. RX PubMed=9878398; DOI=10.1006/jmbi.1998.2316; RA Quevillon S., Robinson J.-C., Berthonneau E., Siatecka M., Mirande M.; RT "Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of RT protein-protein interactions and characterization of a core protein."; RL J. Mol. Biol. 285:183-195(1999). RN [10] RP BIDIRECTIONAL PROMOTER WITH TERF2IP. RX PubMed=14659874; DOI=10.1016/j.gene.2003.08.026; RA Tan M., Wei C., Price C.M.; RT "The telomeric protein Rap1 is conserved in vertebrates and is expressed RT from a bidirectional promoter positioned between the Rap1 and KARS genes."; RL Gene 323:1-10(2003). RN [11] RP INTERACTION WITH MITF, AND FUNCTION. RX PubMed=14975237; DOI=10.1016/s1074-7613(04)00020-2; RA Lee Y.N., Nechushtan H., Figov N., Razin E.; RT "The function of lysyl-tRNA synthetase and Ap4A as signaling regulators of RT MITF activity in FcepsilonRI-activated mast cells."; RL Immunity 20:145-151(2004). RN [12] RP SUBUNIT, AND INTERACTION WITH HIV-1 GAG. RX PubMed=12756246; DOI=10.1074/jbc.m301840200; RA Javanbakht H., Halwani R., Cen S., Saadatmand J., Musier-Forsyth K., RA Gottlinger H., Kleiman L.; RT "The interaction between HIV-1 Gag and human lysyl-tRNA synthetase during RT viral assembly."; RL J. Biol. Chem. 278:27644-27651(2003). RN [13] RP SUBCELLULAR LOCATION, MUTAGENESIS OF 1-MET--GLY-65, INTERACTION WITH AIMP2 RP AND HIV-1 GAG, AND DOMAIN. RX PubMed=15220430; DOI=10.1128/jvi.78.14.7553-7564.2004; RA Halwani R., Cen S., Javanbakht H., Saadatmand J., Kim S., Shiba K., RA Kleiman L.; RT "Cellular distribution of Lysyl-tRNA synthetase and its interaction with RT Gag during human immunodeficiency virus type 1 assembly."; RL J. Virol. 78:7553-7564(2004). RN [14] RP SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=15851690; DOI=10.1073/pnas.0500226102; RA Park S.G., Kim H.J., Min Y.H., Choi E.-C., Shin Y.K., Park B.-J., Lee S.W., RA Kim S.; RT "Human lysyl-tRNA synthetase is secreted to trigger proinflammatory RT response."; RL Proc. Natl. Acad. Sci. U.S.A. 102:6356-6361(2005). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH EEF1A1; AIMP2 AND DARS, AND RP DOMAIN. RX PubMed=18029264; DOI=10.1016/j.bbrc.2007.11.028; RA Guzzo C.M., Yang D.C.H.; RT "Lysyl-tRNA synthetase interacts with EF1alpha, aspartyl-tRNA synthetase RT and p38 in vitro."; RL Biochem. Biophys. Res. Commun. 365:718-723(2008). RN [16] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [17] RP SUBUNIT, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=19131329; DOI=10.1074/jbc.m809636200; RA Kaminska M., Havrylenko S., Decottignies P., Gillet S., Le Marechal P., RA Negrutskii B., Mirande M.; RT "Dissection of the structural organization of the aminoacyl-tRNA synthetase RT complex."; RL J. Biol. Chem. 284:6053-6060(2009). RN [18] RP SUBCELLULAR LOCATION, AND SUBUNIT. RX PubMed=19289464; DOI=10.1074/jbc.m900480200; RA Kaminska M., Havrylenko S., Decottignies P., Le Marechal P., Negrutskii B., RA Mirande M.; RT "Dynamic Organization of Aminoacyl-tRNA Synthetase Complexes in the RT Cytoplasm of Human Cells."; RL J. Biol. Chem. 284:13746-13754(2009). RN [19] RP FUNCTION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT SER-207, AND MUTAGENESIS RP OF SER-207. RX PubMed=19524539; DOI=10.1016/j.molcel.2009.05.019; RA Yannay-Cohen N., Carmi-Levy I., Kay G., Yang C.M., Han J.M., Kemeny D.M., RA Kim S., Nechushtan H., Razin E.; RT "LysRS serves as a key signaling molecule in the immune response by RT regulating gene expression."; RL Mol. Cell 34:603-611(2009). RN [20] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-88 AND LYS-141, 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 [21] 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 [22] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [23] RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [24] RP IDENTIFICATION IN THE MSC COMPLEX, INTERACTION WITH TARSL2, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=24312579; DOI=10.1371/journal.pone.0081734; RA Kim K., Park S.J., Na S., Kim J.S., Choi H., Kim Y.K., Paek E., Lee C.; RT "Reinvestigation of aminoacyl-tRNA synthetase core complex by affinity RT purification-mass spectrometry reveals TARSL2 as a potential member of the RT complex."; RL PLoS ONE 8:E81734-E81734(2013). RN [25] 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 [26] RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 70-581 IN COMPLEX WITH AIMP2; RP LYSINE AND ATP, AND SUBUNIT. RX PubMed=18272479; DOI=10.1073/pnas.0712072105; RA Guo M., Ignatov M., Musier-Forsyth K., Schimmel P., Yang X.-L.; RT "Crystal structure of tetrameric form of human lysyl-tRNA synthetase: RT Implications for multisynthetase complex formation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:2331-2336(2008). RN [27] {ECO:0007744|PDB:4DPG} RP X-RAY CRYSTALLOGRAPHY (2.84 ANGSTROMS) OF 70-581 IN COMPLEX WITH AIMP2; RP LYSINE AND ATP ANALOG, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, INTERACTION RP WITH MITF, SUBCELLULAR LOCATION, AND MUTAGENESIS OF VAL-101; SER-207 AND RP GLY-540. RX PubMed=23159739; DOI=10.1016/j.molcel.2012.10.010; RA Ofir-Birin Y., Fang P., Bennett S.P., Zhang H.M., Wang J., Rachmin I., RA Shapiro R., Song J., Dagan A., Pozo J., Kim S., Marshall A.G., Schimmel P., RA Yang X.L., Nechushtan H., Razin E., Guo M.; RT "Structural switch of lysyl-tRNA synthetase between translation and RT transcription."; RL Mol. Cell 49:30-42(2013). RN [28] {ECO:0007744|PDB:4YCU, ECO:0007744|PDB:4YCW} RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 70-581 IN COMPLEXES WITH AIMP2; RP LYSINE AND THE INHIBITOR CLADOSPORIN. RX PubMed=26074468; DOI=10.1016/j.chembiol.2015.05.007; RA Fang P., Han H., Wang J., Chen K., Chen X., Guo M.; RT "Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP RT Competitive Inhibitor."; RL Chem. Biol. 22:734-744(2015). RN [29] RP VARIANTS CMTRIB HIS-105 AND MET-274, AND VARIANT SER-595. RX PubMed=20920668; DOI=10.1016/j.ajhg.2010.09.008; RA McLaughlin H.M., Sakaguchi R., Liu C., Igarashi T., Pehlivan D., Chu K., RA Iyer R., Cruz P., Cherukuri P.F., Hansen N.F., Mullikin J.C., RA Biesecker L.G., Wilson T.E., Ionasescu V., Nicholson G., Searby C., RA Talbot K., Vance J.M., Zuchner S., Szigeti K., Lupski J.R., Hou Y.M., RA Green E.D., Antonellis A.; RT "Compound heterozygosity for loss-of-function lysyl-tRNA synthetase RT mutations in a patient with peripheral neuropathy."; RL Am. J. Hum. Genet. 87:560-566(2010). RN [30] RP VARIANTS DFNB89 HIS-145 AND ASN-349. RX PubMed=23768514; DOI=10.1016/j.ajhg.2013.05.018; RG University of Washington Center for Mendelian Genomics; RA Santos-Cortez R.L., Lee K., Azeem Z., Antonellis P.J., Pollock L.M., RA Khan S., Ullah I., Andrade-Elizondo P.B., Chiu I., Adams M.D., Basit S., RA Smith J.D., Nickerson D.A., McDermott B.M. Jr., Ahmad W., Leal S.M.; RT "Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal- RT recessive nonsyndromic hearing impairment DFNB89."; RL Am. J. Hum. Genet. 93:132-140(2013). RN [31] RP INVOLVEMENT IN LEPID, AND VARIANTS LEPID TRP-438 AND LYS-525. RX PubMed=25330800; DOI=10.1177/0883073814553272; RG FORGE Canada Consortium; RA McMillan H.J., Humphreys P., Smith A., Schwartzentruber J., Chakraborty P., RA Bulman D.E., Beaulieu C.L., Majewski J., Boycott K.M., Geraghty M.T.; RT "Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl- RT Transfer Ribonucleic Acid (RNA) Synthetase (KARS) Mutations: The Expanding RT Phenotype of Aminoacyl-Transfer RNA Synthetase Mutations in Human RT Disease."; RL J. Child Neurol. 30:1037-1043(2015). RN [32] RP VARIANTS HIS-350 AND ARG-390. RX PubMed=27891585; DOI=10.1111/cge.12931; RA Verrigni D., Diodato D., Di Nottia M., Torraco A., Bellacchio E., Rizza T., RA Tozzi G., Verardo M., Piemonte F., Tasca G., D'Amico A., Bertini E., RA Carrozzo R.; RT "Novel mutations in KARS cause hypertrophic cardiomyopathy and combined RT mitochondrial respiratory chain defect."; RL Clin. Genet. 91:918-923(2017). RN [33] RP INVOLVEMENT IN DEAPLE, VARIANTS DEAPLE HIS-477 AND SER-505, RP CHARACTERIZATION OF VARIANTS DEAPLE HIS-477 AND SER-505, MUTAGENESIS OF RP ASP-346, SUBCELLULAR LOCATION, FUNCTION, COMPONENT OF A SUBUNIT COMPLEX, RP SUBUNIT, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=28887846; DOI=10.1002/humu.23335; RA Zhou X.L., He L.X., Yu L.J., Wang Y., Wang X.J., Wang E.D., Yang T.; RT "Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: RT Potential pathogenic mechanism."; RL Hum. Mutat. 38:1740-1750(2017). RN [34] RP INVOLVEMENT IN LEPID, AND VARIANT LEPID LEU-200. RX PubMed=30252186; DOI=10.1002/humu.23657; RA Ruzzenente B., Assouline Z., Barcia G., Rio M., Boddaert N., Munnich A., RA Roetig A., Metodiev M.D.; RT "Inhibition of mitochondrial translation in fibroblasts from a patient RT expressing the KARS p.(Pro228Leu) variant and presenting with sensorineural RT deafness, developmental delay, and lactic acidosis."; RL Hum. Mutat. 39:2047-2059(2018). RN [35] RP INVOLVEMENT IN LEPID, AND VARIANT LEPID HIS-477. RX PubMed=29615062; DOI=10.1186/s13023-018-0788-4; RA Ardissone A., Tonduti D., Legati A., Lamantea E., Barone R., Dorboz I., RA Boespflug-Tanguy O., Nebbia G., Maggioni M., Garavaglia B., Moroni I., RA Farina L., Pichiecchio A., Orcesi S., Chiapparini L., Ghezzi D.; RT "KARS-related diseases: progressive leukoencephalopathy with brainstem and RT spinal cord calcifications as new phenotype and a review of literature."; RL Orphanet J. Rare Dis. 13:45-45(2018). RN [36] RP INVOLVEMENT IN LEPID, VARIANTS LEPID ASP-189 AND PHE-568, AND RP CHARACTERIZATION OF VARIANT LEPID VARIANTS LEPID ASP-189 AND PHE-568. RX PubMed=30715177; DOI=10.1093/brain/awz001; RA Itoh M., Dai H., Horike S.I., Gonzalez J., Kitami Y., Meguro-Horike M., RA Kuki I., Shimakawa S., Yoshinaga H., Ota Y., Okazaki T., Maegaki Y., RA Nabatame S., Okazaki S., Kawawaki H., Ueno N., Goto Y.I., Kato Y.; RT "Biallelic KARS pathogenic variants cause an early-onset progressive RT leukodystrophy."; RL Brain 142:560-573(2019). RN [37] RP INVOLVEMENT IN DEAPLE, VARIANTS DEAPLE LEU-200 AND VAL-263, RP CHARACTERIZATION OF VARIANTS DEAPLE LEU-200 AND VAL-263, AND INTERACTION RP WITH AIMP2. RX PubMed=31116475; DOI=10.1002/humu.23799; RA Scheidecker S., Baer S., Stoetzel C., Geoffroy V., Lannes B., Rinaldi B., RA Fischer F., Becker H.D., Pelletier V., Pagan C., Acquaviva-Bourdain C., RA Kremer S., Mirande M., Tranchant C., Muller J., Friant S., Dollfus H.; RT "Mutations in KARS cause a severe neurological and neurosensory disease RT with optic neuropathy."; RL Hum. Mutat. 40:1826-1840(2019). RN [38] RP INVOLVEMENT IN DEAPLE, AND VARIANTS DEAPLE HIS-80 AND PHE-448. RX PubMed=30737337; DOI=10.1212/wnl.0000000000007098; RA van der Knaap M.S., Bugiani M., Mendes M.I., Riley L.G., Smith D.E.C., RA Rudinger-Thirion J., Frugier M., Breur M., Crawford J., van Gaalen J., RA Schouten M., Willems M., Waisfisz Q., Mau-Them F.T., Rodenburg R.J., RA Taft R.J., Keren B., Christodoulou J., Depienne C., Simons C., RA Salomons G.S., Mochel F.; RT "Biallelic variants in LARS2 and KARS cause deafness and RT (ovario)leukodystrophy."; RL Neurology 92:e1225-e1237(2019). CC -!- FUNCTION: Catalyzes the specific attachment of an amino acid to its CC cognate tRNA in a 2 step reaction: the amino acid (AA) is first CC activated by ATP to form AA-AMP and then transferred to the acceptor CC end of the tRNA (PubMed:9278442, PubMed:18029264, PubMed:18272479). CC When secreted, acts as a signaling molecule that induces immune CC response through the activation of monocyte/macrophages CC (PubMed:15851690). Catalyzes the synthesis of the signaling molecule CC diadenosine tetraphosphate (Ap4A), and thereby mediates disruption of CC the complex between HINT1 and MITF and the concomitant activation of CC MITF transcriptional activity (PubMed:5338216, PubMed:14975237, CC PubMed:19524539, PubMed:23159739). {ECO:0000269|PubMed:14975237, CC ECO:0000269|PubMed:15851690, ECO:0000269|PubMed:18029264, CC ECO:0000269|PubMed:19524539, ECO:0000269|PubMed:28887846, CC ECO:0000269|PubMed:5338216, ECO:0000269|PubMed:9278442}. CC -!- FUNCTION: (Microbial infection) Interacts with HIV-1 virus GAG protein, CC facilitating the selective packaging of tRNA(3)(Lys), the primer for CC reverse transcription initiation. {ECO:0000269|PubMed:15220430}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-lysine + tRNA(Lys) = AMP + diphosphate + L-lysyl- CC tRNA(Lys); Xref=Rhea:RHEA:20792, Rhea:RHEA-COMP:9696, Rhea:RHEA- CC COMP:9697, ChEBI:CHEBI:30616, ChEBI:CHEBI:32551, ChEBI:CHEBI:33019, CC ChEBI:CHEBI:78442, ChEBI:CHEBI:78529, ChEBI:CHEBI:456215; EC=6.1.1.6; CC Evidence={ECO:0000269|PubMed:18029264, ECO:0000269|PubMed:23159739, CC ECO:0000269|PubMed:9278442}; CC -!- ACTIVITY REGULATION: Up-regulated by DARS and EEF1A1, but not by AIMP2. CC {ECO:0000269|PubMed:18029264}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.19 uM for tRNA(Lys) {ECO:0000269|PubMed:28887846}; CC Note=kcat is 0.31 sec(-1) for aminoacylation for tRNA(Lys). CC {ECO:0000269|PubMed:28887846}; CC -!- SUBUNIT: Homodimer and tetradimer (PubMed:18272479, PubMed:23159739, CC PubMed:26074468, PubMed:28887846). Part of the multisynthetase complex CC (MSC), a multisubunit complex that groups tRNA ligases for Arg (RARS), CC Asp (DARS), Gln (QARS), Ile (IARS), Leu (LARS), Lys (KARS), Met (MARS) CC the bifunctional ligase for Glu and Pro (EPRS) and the auxiliary CC subunits AIMP1/p43, AIMP2/p38 and EEF1E1/p18 (PubMed:19131329, CC PubMed:19289464, PubMed:24312579, PubMed:23159739). Interacts with CC AIMP2 (via N-terminus) and MITF (PubMed:9878398, PubMed:14975237, CC PubMed:15220430, PubMed:23159739, PubMed:26074468, PubMed:31116475). CC Interacts with TARSL2 (PubMed:24312579). {ECO:0000269|PubMed:14975237, CC ECO:0000269|PubMed:15220430, ECO:0000269|PubMed:18029264, CC ECO:0000269|PubMed:18272479, ECO:0000269|PubMed:19131329, CC ECO:0000269|PubMed:19289464, ECO:0000269|PubMed:23159739, CC ECO:0000269|PubMed:24312579, ECO:0000269|PubMed:26074468, CC ECO:0000269|PubMed:28887846, ECO:0000269|PubMed:9878398}. CC -!- SUBUNIT: (Microbial infection) Interacts directly with HIV-1 virus GAG CC protein (PubMed:12756246, PubMed:15220430). CC {ECO:0000269|PubMed:12756246, ECO:0000269|PubMed:15220430}. CC -!- INTERACTION: CC Q15046; Q13155: AIMP2; NbExp=21; IntAct=EBI-356367, EBI-745226; CC Q15046; P07814: EPRS1; NbExp=4; IntAct=EBI-356367, EBI-355315; CC Q15046; Q15046: KARS1; NbExp=6; IntAct=EBI-356367, EBI-356367; CC Q15046; P08865: RPSA; NbExp=9; IntAct=EBI-356367, EBI-354112; CC Q15046; P00441: SOD1; NbExp=3; IntAct=EBI-356367, EBI-990792; CC Q15046-1; Q13155: AIMP2; NbExp=2; IntAct=EBI-21457670, EBI-745226; CC -!- SUBCELLULAR LOCATION: [Isoform Cytoplasmic]: Cytoplasm, cytosol CC {ECO:0000269|PubMed:10952987, ECO:0000269|PubMed:19289464, CC ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:28887846}. Cytoplasm CC {ECO:0000269|PubMed:15220430}. Nucleus {ECO:0000269|PubMed:15220430, CC ECO:0000269|PubMed:23159739}. Cell membrane CC {ECO:0000269|PubMed:15220430}; Peripheral membrane protein CC {ECO:0000269|PubMed:15220430}. Secreted {ECO:0000269|PubMed:15851690}. CC Note=Secretion is induced by TNF-alpha (PubMed:15851690). Cytosolic in CC quiescent mast cells. Translocates into the nucleus in response to mast CC cell activation by immunoglobulin E (PubMed:23159739). CC {ECO:0000269|PubMed:15851690, ECO:0000269|PubMed:23159739}. CC -!- SUBCELLULAR LOCATION: [Isoform Mitochondrial]: Mitochondrion CC {ECO:0000269|PubMed:10952987}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Cytoplasmic; CC IsoId=Q15046-1; Sequence=Displayed; CC Name=Mitochondrial; CC IsoId=Q15046-2; Sequence=VSP_038481; CC -!- DOMAIN: The N-terminal domain (1-65) of the cytoplasmic isoform is a CC functional tRNA-binding domain, is required for nuclear localization, CC is involved in the interaction with DARS, but has a repulsive role in CC the binding to EEF1A1. A central domain (208-259) is involved in CC homodimerization and is required for interaction with HIV-1 GAG and CC incorporation into virions. The C-terminal domain (452-597) is not CC required for interaction with AIMP2. {ECO:0000269|PubMed:15220430, CC ECO:0000269|PubMed:18029264}. CC -!- PTM: Phosphorylated on a serine residue after mast cell stimulation CC with immunoglobulin E (IgE). {ECO:0000250|UniProtKB:Q5XIM7}. CC -!- DISEASE: Charcot-Marie-Tooth disease, recessive intermediate B (CMTRIB) CC [MIM:613641]: A 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. Recessive intermediate forms of Charcot-Marie- CC Tooth disease are characterized by clinical and pathologic features CC intermediate between demyelinating and axonal peripheral neuropathies, CC and motor median nerve conduction velocities ranging from 25 to 45 CC m/sec. {ECO:0000269|PubMed:20920668}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Deafness, autosomal recessive, 89 (DFNB89) [MIM:613916]: A CC form of non-syndromic deafness characterized by bilateral, prelingual, CC moderate to severe hearing loss affecting all frequencies. CC {ECO:0000269|PubMed:23768514}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Deafness, congenital, and adult-onset progressive CC leukoencephalopathy (DEAPLE) [MIM:619196]: An autosomal recessive, CC complex neurodegenerative disorder characterized by congenital CC sensorineural deafness, and progressive motor and cognitive decline CC apparent in young adulthood. Brain imaging shows diffuse white matter CC abnormalities affecting various brain regions, consistent with a CC progressive leukoencephalopathy. More variable additional features may CC include visual impairment and axonal peripheral neuropathy. Premature CC death may occurr in some patients. {ECO:0000269|PubMed:28887846, CC ECO:0000269|PubMed:30737337, ECO:0000269|PubMed:31116475}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Leukoencephalopathy, progressive, infantile-onset, with or CC without deafness (LEPID) [MIM:619147]: An autosomal recessive, complex CC neurodegenerative disorder apparent from infancy. LEPID is CC characterized by early-onset progressive leukoencephalopathy with CC brainstem and spinal cord calcifications, sensorineural deafness in CC most patients, global developmental delay with cognitive impairment and CC poor or absent speech, developmental regression, and neurologic CC deterioration. Additional more variable features may include poor CC overall growth with microcephaly, seizures, visual loss, microcytic CC anemia, and hepatic enlargement or abnormal liver enzymes. Premature CC death is common. {ECO:0000269|PubMed:25330800, CC ECO:0000269|PubMed:29615062, ECO:0000269|PubMed:30252186, CC ECO:0000269|PubMed:30715177}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Shares a bidirectional promoter with TERF2IP/RAP1. CC {ECO:0000305|PubMed:14659874}. CC -!- MISCELLANEOUS: [Isoform Mitochondrial]: Mitochondrial precursor. CC Contains a mitochondrial transit peptide at positions 1-16. CC {ECO:0000305}. CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA06688.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; 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; D32053; BAA22084.1; -; mRNA. DR EMBL; AF285758; AAG30114.1; -; mRNA. DR EMBL; D31890; BAA06688.1; ALT_INIT; mRNA. DR EMBL; AC025287; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471114; EAW95622.1; -; Genomic_DNA. DR EMBL; CH471114; EAW95624.1; -; Genomic_DNA. DR EMBL; BC004132; AAH04132.1; -; mRNA. DR CCDS; CCDS10923.1; -. [Q15046-1] DR CCDS; CCDS45532.1; -. [Q15046-2] DR RefSeq; NP_001123561.1; NM_001130089.1. [Q15046-2] DR RefSeq; NP_005539.1; NM_005548.2. [Q15046-1] DR PDB; 3BJU; X-ray; 2.31 A; A/B/C/D=70-582. DR PDB; 4DPG; X-ray; 2.84 A; A/B/C/D/E/F/G/H=70-581. DR PDB; 4YCU; X-ray; 2.10 A; A/B=70-581. DR PDB; 4YCW; X-ray; 2.90 A; A/B/E/F=70-581. DR PDB; 6CHD; X-ray; 2.50 A; A/B=1-597. DR PDB; 6ILD; X-ray; 1.88 A; A/B=70-581. DR PDB; 6ILH; X-ray; 2.50 A; A/B=70-581. DR PDB; 7EA9; X-ray; 2.50 A; A/B/C/D=70-581. DR PDBsum; 3BJU; -. DR PDBsum; 4DPG; -. DR PDBsum; 4YCU; -. DR PDBsum; 4YCW; -. DR PDBsum; 6CHD; -. DR PDBsum; 6ILD; -. DR PDBsum; 6ILH; -. DR PDBsum; 7EA9; -. DR AlphaFoldDB; Q15046; -. DR BMRB; Q15046; -. DR SMR; Q15046; -. DR BioGRID; 109938; 370. DR ComplexPortal; CPX-2469; Multiaminoacyl-tRNA synthetase complex. DR CORUM; Q15046; -. DR DIP; DIP-29725N; -. DR IntAct; Q15046; 82. DR MINT; Q15046; -. DR STRING; 9606.ENSP00000325448; -. DR BindingDB; Q15046; -. DR ChEMBL; CHEMBL5575; -. DR DrugBank; DB00123; Lysine. DR DrugCentral; Q15046; -. DR MoonProt; Q15046; -. DR CarbonylDB; Q15046; -. DR GlyCosmos; Q15046; 2 sites, 1 glycan. DR GlyGen; Q15046; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q15046; -. DR MetOSite; Q15046; -. DR PhosphoSitePlus; Q15046; -. DR SwissPalm; Q15046; -. DR BioMuta; KARS; -. DR DMDM; 20178333; -. DR CPTAC; CPTAC-231; -. DR EPD; Q15046; -. DR jPOST; Q15046; -. DR MassIVE; Q15046; -. DR MaxQB; Q15046; -. DR PaxDb; 9606-ENSP00000325448; -. DR PeptideAtlas; Q15046; -. DR ProteomicsDB; 60395; -. [Q15046-1] DR ProteomicsDB; 60396; -. [Q15046-2] DR Pumba; Q15046; -. DR ABCD; Q15046; 3 sequenced antibodies. DR Antibodypedia; 16841; 279 antibodies from 36 providers. DR DNASU; 3735; -. DR Ensembl; ENST00000302445.8; ENSP00000303043.3; ENSG00000065427.15. [Q15046-1] DR Ensembl; ENST00000319410.9; ENSP00000325448.5; ENSG00000065427.15. [Q15046-2] DR GeneID; 3735; -. DR KEGG; hsa:3735; -. DR MANE-Select; ENST00000302445.8; ENSP00000303043.3; NM_005548.3; NP_005539.1. DR UCSC; uc002feq.4; human. [Q15046-1] DR AGR; HGNC:6215; -. DR CTD; 3735; -. DR DisGeNET; 3735; -. DR GeneCards; KARS1; -. DR HGNC; HGNC:6215; KARS1. DR HPA; ENSG00000065427; Low tissue specificity. DR MalaCards; KARS1; -. DR MIM; 601421; gene. DR MIM; 613641; phenotype. DR MIM; 613916; phenotype. DR MIM; 619147; phenotype. DR MIM; 619196; phenotype. DR neXtProt; NX_Q15046; -. DR OpenTargets; ENSG00000065427; -. DR Orphanet; 254334; Autosomal recessive intermediate Charcot-Marie-Tooth disease type B. DR Orphanet; 3240; Early-onset progressive leukoencephalopathy-central nervous system calcification-deafness-visual impairment syndrome. DR Orphanet; 90636; Rare autosomal recessive non-syndromic sensorineural deafness type DFNB. DR PharmGKB; PA30016; -. DR VEuPathDB; HostDB:ENSG00000065427; -. DR eggNOG; KOG1885; Eukaryota. DR GeneTree; ENSGT01030000234618; -. DR HOGENOM; CLU_008255_6_0_1; -. DR InParanoid; Q15046; -. DR OMA; DFRNEGM; -. DR OrthoDB; 648039at2759; -. DR PhylomeDB; Q15046; -. DR TreeFam; TF300365; -. DR BRENDA; 6.1.1.6; 2681. DR PathwayCommons; Q15046; -. DR Reactome; R-HSA-2408522; Selenoamino acid metabolism. DR Reactome; R-HSA-379716; Cytosolic tRNA aminoacylation. DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation. DR SABIO-RK; Q15046; -. DR SignaLink; Q15046; -. DR SIGNOR; Q15046; -. DR BioGRID-ORCS; 3735; 824 hits in 1167 CRISPR screens. DR ChiTaRS; KARS; human. DR EvolutionaryTrace; Q15046; -. DR GeneWiki; KARS_(gene); -. DR GenomeRNAi; 3735; -. DR Pharos; Q15046; Tchem. DR PRO; PR:Q15046; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q15046; Protein. DR Bgee; ENSG00000065427; Expressed in gingival epithelium and 215 other cell types or tissues. DR ExpressionAtlas; Q15046; baseline and differential. DR GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005615; C:extracellular space; IDA:CAFA. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0016597; F:amino acid binding; IEA:Ensembl. DR GO; GO:0003877; F:ATP adenylyltransferase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0004824; F:lysine-tRNA ligase activity; IDA:UniProtKB. DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB. DR GO; GO:0000049; F:tRNA binding; IBA:GO_Central. DR GO; GO:0002276; P:basophil activation involved in immune response; IGI:CAFA. DR GO; GO:0015966; P:diadenosine tetraphosphate biosynthetic process; IDA:UniProtKB. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IGI:CAFA. DR GO; GO:0006430; P:lysyl-tRNA aminoacylation; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IGI:CAFA. DR GO; GO:0002863; P:positive regulation of inflammatory response to antigenic stimulus; IDA:CAFA. DR GO; GO:0043032; P:positive regulation of macrophage activation; IDA:CAFA. DR GO; GO:0010165; P:response to X-ray; IEA:Ensembl. DR GO; GO:0008033; P:tRNA processing; NAS:UniProtKB. DR CDD; cd00775; LysRS_core; 1. DR CDD; cd04322; LysRS_N; 1. DR DisProt; DP02382; -. DR Gene3D; 2.40.50.140; Nucleic acid-binding proteins; 1. DR HAMAP; MF_00252; Lys_tRNA_synth_class2; 1. DR InterPro; IPR004364; Aa-tRNA-synt_II. DR InterPro; IPR006195; aa-tRNA-synth_II. DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL. DR InterPro; IPR002313; Lys-tRNA-ligase_II. DR InterPro; IPR034762; Lys-tRNA-ligase_II_bac/euk. DR InterPro; IPR044136; Lys-tRNA-ligase_II_N. DR InterPro; IPR018149; Lys-tRNA-synth_II_C. DR InterPro; IPR012340; NA-bd_OB-fold. DR InterPro; IPR004365; NA-bd_OB_tRNA. DR NCBIfam; TIGR00499; lysS_bact; 1. DR PANTHER; PTHR42918:SF9; LYSINE--TRNA LIGASE; 1. DR PANTHER; PTHR42918; LYSYL-TRNA SYNTHETASE; 1. DR Pfam; PF00152; tRNA-synt_2; 1. DR Pfam; PF01336; tRNA_anti-codon; 1. DR PIRSF; PIRSF039101; LysRS2; 1. DR PRINTS; PR00982; TRNASYNTHLYS. DR SUPFAM; SSF55681; Class II aaRS and biotin synthetases; 1. DR SUPFAM; SSF50249; Nucleic acid-binding proteins; 1. DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1. DR Genevisible; Q15046; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Aminoacyl-tRNA synthetase; KW ATP-binding; Cell membrane; Charcot-Marie-Tooth disease; Cytoplasm; KW Deafness; Direct protein sequencing; Disease variant; KW Host-virus interaction; Intellectual disability; Ligase; Membrane; KW Mitochondrion; Neurodegeneration; Neuropathy; Non-syndromic deafness; KW Nucleotide-binding; Nucleus; Phosphoprotein; Protein biosynthesis; KW Reference proteome; Secreted; Transferase. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.7, ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378" FT CHAIN 2..597 FT /note="Lysine--tRNA ligase" FT /id="PRO_0000152765" FT REGION 1..71 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 13..44 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 45..64 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 277 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18272479, FT ECO:0000269|PubMed:26074468" FT BINDING 301 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18272479, FT ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:26074468" FT BINDING 323..325 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:18272479" FT BINDING 331..332 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:18272479" FT BINDING 339 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18272479, FT ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:26074468" FT BINDING 341 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18272479, FT ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:26074468" FT BINDING 494..495 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:18272479" FT BINDING 497 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18272479, FT ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:26074468" FT BINDING 501 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:18272479, FT ECO:0000269|PubMed:23159739, ECO:0000269|PubMed:26074468" FT BINDING 550..553 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:18272479" FT MOD_RES 2 FT /note="N-acetylalanine" FT /evidence="ECO:0000269|Ref.7, ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378" FT MOD_RES 88 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 141 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT MOD_RES 207 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:19524539" FT MOD_RES 590 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q99MN1" FT MOD_RES 591 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q99MN1" FT MOD_RES 596 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q99MN1" FT VAR_SEQ 1..21 FT /note="MAAVQAAEVKVDGSEPKLSKN -> MLTQAAVRLVRGSLRKTSWAEWGHREL FT RLGQLAPFTAPHKDKSFSDQRS (in isoform Mitochondrial)" FT /evidence="ECO:0000303|PubMed:10952987" FT /id="VSP_038481" FT VARIANT 80 FT /note="R -> H (in DEAPLE; uncertain significance; FT dbSNP:rs369114426)" FT /evidence="ECO:0000269|PubMed:30737337" FT /id="VAR_085386" FT VARIANT 105 FT /note="L -> H (in CMTRIB; severely affects enzyme activity; FT dbSNP:rs267607194)" FT /evidence="ECO:0000269|PubMed:20920668" FT /id="VAR_064911" FT VARIANT 145 FT /note="Y -> H (in DFNB89; dbSNP:rs397514745)" FT /evidence="ECO:0000269|PubMed:23768514" FT /id="VAR_070233" FT VARIANT 179 FT /note="G -> A (in dbSNP:rs11557665)" FT /id="VAR_052640" FT VARIANT 189 FT /note="G -> D (in LEPID; does not rescue the developmental FT defects caused by KARS1 depletion in xenopus)" FT /evidence="ECO:0000269|PubMed:30715177" FT /id="VAR_085387" FT VARIANT 200 FT /note="P -> L (in DEAPLE and LEPID; reduces interaction FT with AIMP2. Reduces tRNA-lysine aminoacylation)" FT /evidence="ECO:0000269|PubMed:30252186, FT ECO:0000269|PubMed:31116475" FT /id="VAR_085388" FT VARIANT 263 FT /note="F -> V (in DEAPLE; reduces interaction with AIMP2. FT Reduces tRNA-lysine aminoacylation; dbSNP:rs772410450)" FT /evidence="ECO:0000269|PubMed:31116475" FT /id="VAR_085389" FT VARIANT 274 FT /note="I -> M (in CMTRIB; dbSNP:rs146955132)" FT /evidence="ECO:0000269|PubMed:20920668" FT /id="VAR_064912" FT VARIANT 349 FT /note="D -> N (in DFNB89; dbSNP:rs397514746)" FT /evidence="ECO:0000269|PubMed:23768514" FT /id="VAR_070234" FT VARIANT 350 FT /note="L -> H (found in a patient with hypertrophic FT cardiomyopathy and mild intellectual disability together FT with proximal muscle weakness; uncertain significance)" FT /evidence="ECO:0000269|PubMed:27891585" FT /id="VAR_079741" FT VARIANT 390 FT /note="P -> R (found in a patient with hypertrophic FT cardiomyopathy and mild intellectual disability together FT with proximal muscle weakness; uncertain significance)" FT /evidence="ECO:0000269|PubMed:27891585" FT /id="VAR_079742" FT VARIANT 438 FT /note="R -> W (in LEPID; uncertain significance; FT dbSNP:rs761527468)" FT /evidence="ECO:0000269|PubMed:25330800" FT /id="VAR_079743" FT VARIANT 448 FT /note="V -> F (in DEAPLE; uncertain significance)" FT /evidence="ECO:0000269|PubMed:30737337" FT /id="VAR_085390" FT VARIANT 477 FT /note="R -> H (in DEAPLE and LEPID; decreases tRNA-lysine FT aminoacylation; induces protein aggregation; releases from FT the subunit complex; no effect on cytoplasmic location; no FT effect on oligomerization; dbSNP:rs778748895)" FT /evidence="ECO:0000269|PubMed:28887846, FT ECO:0000269|PubMed:29615062" FT /id="VAR_079744" FT VARIANT 505 FT /note="P -> S (in DEAPLE; decreases tRNA-lysine FT aminoacylation; slightly induces protein aggregation; no FT effect on cytoplasmic location; no effect on FT oligomerization; dbSNP:rs1555512658)" FT /evidence="ECO:0000269|PubMed:28887846" FT /id="VAR_079745" FT VARIANT 525 FT /note="E -> K (in LEPID; uncertain significance; FT dbSNP:rs770522582)" FT /evidence="ECO:0000269|PubMed:25330800" FT /id="VAR_079746" FT VARIANT 568 FT /note="L -> F (in LEPID; decreases tRNA-lysine FT aminoacylation activity of both the mitochondrial and FT cytosolic forms. Does not rescue the developmental defects FT caused by KARS1 depletion in xenopus)" FT /evidence="ECO:0000269|PubMed:30715177" FT /id="VAR_085391" FT VARIANT 595 FT /note="T -> S (in dbSNP:rs6834)" FT /evidence="ECO:0000269|PubMed:10952987, FT ECO:0000269|PubMed:20920668, ECO:0000269|PubMed:7584044" FT /id="VAR_016105" FT MUTAGEN 1..65 FT /note="Missing: Loss of nuclear localization, but no effect FT on packaging into HIV-1." FT /evidence="ECO:0000269|PubMed:15220430" FT MUTAGEN 101 FT /note="V->D,R,W: Disrupts interaction with AIMP2 and the FT multisynthase complex." FT /evidence="ECO:0000269|PubMed:23159739" FT MUTAGEN 207 FT /note="S->A: Strongly reduced production of diadenosine FT tetraphosphate (Ap4A). Reduced protein phosphorylation." FT /evidence="ECO:0000269|PubMed:19524539" FT MUTAGEN 207 FT /note="S->D: Phosphomimetic mutant that strongly enhances FT translocation into the nucleus and production of FT diadenosine tetraphosphate (Ap4A). Almost complete loss of FT tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:23159739" FT MUTAGEN 207 FT /note="S->R: Strongly decreased tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:23159739" FT MUTAGEN 207 FT /note="S->Y: Almost complete loss of tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:23159739" FT MUTAGEN 346 FT /note="D->R: Induces protein aggregation. Releases from the FT subunit complex." FT /evidence="ECO:0000269|PubMed:28887846" FT MUTAGEN 540 FT /note="G->Y: Disrupts interaction with AIMP2 and the FT multisynthase complex. Increases production of diadenosine FT tetraphosphate (Ap4A). Almost complete loss of tRNA ligase FT activity." FT /evidence="ECO:0000269|PubMed:23159739" FT HELIX 73..89 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 105..112 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 126..137 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 139..149 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 152..159 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 166..175 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 181..190 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 196..207 FT /evidence="ECO:0007829|PDB:6ILD" FT TURN 216..218 FT /evidence="ECO:0007829|PDB:4YCU" FT HELIX 223..228 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 230..236 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 238..260 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 270..274 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 277..279 FT /evidence="ECO:0007829|PDB:3BJU" FT STRAND 284..287 FT /evidence="ECO:0007829|PDB:6ILD" FT TURN 288..291 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 292..296 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 301..309 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 314..322 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 328..330 FT /evidence="ECO:0007829|PDB:4DPG" FT STRAND 333..343 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 347..366 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 367..373 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 383..386 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 392..395 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 396..404 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 411..413 FT /evidence="ECO:0007829|PDB:3BJU" FT HELIX 417..429 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 440..451 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 453..455 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 460..463 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 467..469 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 477..479 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 482..490 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 493..501 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 505..520 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 524..526 FT /evidence="ECO:0007829|PDB:4YCW" FT HELIX 531..538 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 543..550 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 551..558 FT /evidence="ECO:0007829|PDB:6ILD" FT HELIX 564..567 FT /evidence="ECO:0007829|PDB:6ILD" FT STRAND 568..570 FT /evidence="ECO:0007829|PDB:6CHD" FT CONFLICT Q15046-2:48 FT /note="R -> G (in Ref. 2; AAG30114)" FT /evidence="ECO:0000305" SQ SEQUENCE 597 AA; 68048 MW; E7770953332D905D CRC64; MAAVQAAEVK VDGSEPKLSK NELKRRLKAE KKVAEKEAKQ KELSEKQLSQ ATAAATNHTT DNGVGPEEES VDPNQYYKIR SQAIHQLKVN GEDPYPHKFH VDISLTDFIQ KYSHLQPGDH LTDITLKVAG RIHAKRASGG KLIFYDLRGE GVKLQVMANS RNYKSEEEFI HINNKLRRGD IIGVQGNPGK TKKGELSIIP YEITLLSPCL HMLPHLHFGL KDKETRYRQR YLDLILNDFV RQKFIIRSKI ITYIRSFLDE LGFLEIETPM MNIIPGGAVA KPFITYHNEL DMNLYMRIAP ELYHKMLVVG GIDRVYEIGR QFRNEGIDLT HNPEFTTCEF YMAYADYHDL MEITEKMVSG MVKHITGSYK VTYHPDGPEG QAYDVDFTPP FRRINMVEEL EKALGMKLPE TNLFETEETR KILDDICVAK AVECPPPRTT ARLLDKLVGE FLEVTCINPT FICDHPQIMS PLAKWHRSKE GLTERFELFV MKKEICNAYT ELNDPMRQRQ LFEEQAKAKA AGDDEAMFID ENFCTALEYG LPPTAGWGMG IDRVAMFLTD SNNIKEVLLF PAMKPEDKKE NVATTDTLES TTVGTSV //