SYK_HUMAN
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 03-AUG-2022, entry version 204.
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 type, B
CC (CMTRIB) [MIM:613641]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later of
CC the distal muscles of the arms. Recessive intermediate forms of
CC Charcot-Marie-Tooth disease are characterized by clinical and
CC pathologic features intermediate between demyelinating and axonal
CC peripheral neuropathies, and motor median nerve conduction velocities
CC ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:20920668}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC 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};
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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; 272.
DR CORUM; Q15046; -.
DR DIP; DIP-29725N; -.
DR IntAct; Q15046; 69.
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 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; Q15046; -.
DR PeptideAtlas; Q15046; -.
DR PRIDE; Q15046; -.
DR ProteomicsDB; 60395; -. [Q15046-1]
DR ProteomicsDB; 60396; -. [Q15046-2]
DR ABCD; Q15046; 3 sequenced antibodies.
DR Antibodypedia; 16841; 241 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 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; 90636; 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; EIFGEKC; -.
DR OrthoDB; 837479at2759; -.
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 SignaLink; Q15046; -.
DR SIGNOR; Q15046; -.
DR BioGRID-ORCS; 3735; 787 hits in 1087 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 213 other tissues.
DR ExpressionAtlas; Q15046; baseline and differential.
DR Genevisible; Q15046; HS.
DR GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
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: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:0045893; P:positive regulation of transcription, DNA-templated; IGI: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; -; 1.
DR Gene3D; 3.30.930.10; -; 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 Pfam; PF00152; tRNA-synt_2; 1.
DR Pfam; PF01336; tRNA_anti-codon; 1.
DR PIRSF; PIRSF039101; LysRS2; 1.
DR PRINTS; PR00982; TRNASYNTHLYS.
DR SUPFAM; SSF50249; SSF50249; 1.
DR SUPFAM; SSF55681; SSF55681; 1.
DR TIGRFAMs; TIGR00499; lysS_bact; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
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; unknown pathological
FT significance)"
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)"
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; unknown pathological
FT 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; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:27891585"
FT /id="VAR_079742"
FT VARIANT 438
FT /note="R -> W (in LEPID; unknown pathological significance;
FT dbSNP:rs761527468)"
FT /evidence="ECO:0000269|PubMed:25330800"
FT /id="VAR_079743"
FT VARIANT 448
FT /note="V -> F (in DEAPLE; unknown pathological
FT 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; unknown pathological 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
