ID SYLC_HUMAN Reviewed; 1176 AA. AC Q9P2J5; A2RRR4; A7E266; B4DJ10; Q2TU79; Q9NSE1; DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot. DT 07-JUN-2004, sequence version 2. DT 27-MAR-2024, entry version 198. DE RecName: Full=Leucine--tRNA ligase, cytoplasmic {ECO:0000305}; DE EC=6.1.1.4 {ECO:0000269|PubMed:25051973}; DE AltName: Full=Leucyl-tRNA synthetase {ECO:0000303|PubMed:25051973}; DE Short=LeuRS {ECO:0000303|PubMed:25051973}; DE Short=cLRS {ECO:0000303|PubMed:32232361}; GN Name=LARS1 {ECO:0000312|HGNC:HGNC:6512}; Synonyms=KIAA1352, LARS; 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 LYS-1088. RC TISSUE=Brain; RA Motegi H., Noda T., Shiba K.; RT "Cloning and sequence determination of a human cytoplasmic leucyl-tRNA RT synthetase gene."; RL Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=10718198; DOI=10.1093/dnares/7.1.65; RA Nagase T., Kikuno R., Ishikawa K., Hirosawa M., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XVI. The RT complete sequences of 150 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 7:65-73(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=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 MRNA] (ISOFORM 3). RA Kim J.W., Kim H.K., Shin S.M.; RT "Identification of a human cell proliferation gene."; RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15372022; DOI=10.1038/nature02919; RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S., RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.; RT "The DNA sequence and comparative analysis of human chromosome 5."; RL Nature 431:268-274(2004). RN [6] 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). 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 [8] 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 [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-167 AND SER-720, AND RP IDENTIFICATION BY MASS SPECTROMETRY [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 [10] 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 [11] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF 236-ARG--GLY-256; PRO-242; RP GLY-245; PRO-247; ASP-250; 514-VAL--TYR-534; SER-519; VAL-523; ALA-525 AND RP CYS-527. RX PubMed=25051973; DOI=10.1261/rna.044404.114; RA Huang Q., Zhou X.L., Hu Q.H., Lei H.Y., Fang Z.P., Yao P., Wang E.D.; RT "A bridge between the aminoacylation and editing domains of leucyl-tRNA RT synthetase is crucial for its synthetic activity."; RL RNA 20:1440-1450(2014). RN [12] 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 [13] RP X-RAY CRYSTALLOGRAPHY (3.25 ANGSTROMS) OF 260-509 IN COMPLEX WITH SYNTHETIC RP INHIBITOR AND AMP, AND FUNCTION. RX PubMed=19426743; DOI=10.1016/j.jmb.2009.04.073; RA Seiradake E., Mao W., Hernandez V., Baker S.J., Plattner J.J., RA Alley M.R.K., Cusack S.; RT "Crystal structures of the human and fungal cytosolic Leucyl-tRNA RT synthetase editing domains: A structural basis for the rational design of RT antifungal benzoxaboroles."; RL J. Mol. Biol. 390:196-207(2009). RN [14] RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 1-1070 IN COMPLEX WITH LEUCINE RP ANALOG, FUNCTION, DOMAIN, AND SUBUNIT. RX PubMed=32232361; DOI=10.1093/nar/gkaa189; RA Liu R.J., Long T., Li H., Zhao J., Li J., Wang M., Palencia A., Lin J., RA Cusack S., Wang E.D.; RT "Molecular basis of the multifaceted functions of human leucyl-tRNA RT synthetase in protein synthesis and beyond."; RL Nucleic Acids Res. 48:4946-4959(2020). RN [15] RP VARIANT ILFS1 CYS-373, AND VARIANT ARG-82. RX PubMed=22607940; DOI=10.1016/j.ymgme.2012.04.017; RA Casey J.P., McGettigan P., Lynam-Lennon N., McDermott M., Regan R., RA Conroy J., Bourke B., O'Sullivan J., Crushell E., Lynch S., Ennis S.; RT "Identification of a mutation in LARS as a novel cause of infantile RT hepatopathy."; RL Mol. Genet. Metab. 106:351-358(2012). CC -!- FUNCTION: Aminoacyl-tRNA synthetase that catalyzes the specific CC attachment of leucine to its cognate tRNA (tRNA(Leu)) (PubMed:25051973, CC PubMed:32232361). It performs tRNA aminoacylation in a two-step CC reaction: Leu is initially activated by ATP to form a leucyl-adenylate CC (Leu-AMP) intermediate; then the leucyl moiety is transferred to the CC acceptor 3' end of the tRNA to yield leucyl-tRNA (PubMed:25051973). To CC improve the fidelity of catalytic reactions, it is also able to CC hydrolyze misactivated aminoacyl-adenylate intermediates (pre-transfer CC editing) and mischarged aminoacyl-tRNAs (post-transfer editing) CC (PubMed:25051973). {ECO:0000269|PubMed:19426743, CC ECO:0000269|PubMed:25051973, ECO:0000269|PubMed:32232361}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-leucine + tRNA(Leu) = AMP + diphosphate + L-leucyl- CC tRNA(Leu); Xref=Rhea:RHEA:11688, Rhea:RHEA-COMP:9613, Rhea:RHEA- CC COMP:9622, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57427, CC ChEBI:CHEBI:78442, ChEBI:CHEBI:78494, ChEBI:CHEBI:456215; EC=6.1.1.4; CC Evidence={ECO:0000269|PubMed:25051973}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11689; CC Evidence={ECO:0000305}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + L-methionyl-tRNA(Leu) = H(+) + L-methionine + tRNA(Leu); CC Xref=Rhea:RHEA:77535, Rhea:RHEA-COMP:9613, Rhea:RHEA-COMP:18931, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57844, CC ChEBI:CHEBI:78442, ChEBI:CHEBI:78530; CC Evidence={ECO:0000269|PubMed:25051973}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77536; CC Evidence={ECO:0000269|PubMed:25051973}; CC -!- ACTIVITY REGULATION: 5-fluoro-1,3-dihydro-1-hydroxy-1,2-benzoxaborole CC inhibits LARS1 by forming a covalent adduct with the 3' adenosine of CC tRNA(Leu) at the editing site, thus locking the enzyme in an inactive CC conformation. CC -!- SUBUNIT: Part of the aminoacyl-tRNA synthetase multienzyme complex, CC also known as multisynthetase complex (MSC), that is composed of the CC aminoacyl-tRNA ligases for Arg (RARS1), Asp (DARS1), Gln (QARS1), Ile CC (IARS1), Leu (LARS1), Lys (KARS1), Met (MARS1) the bifunctional ligase CC for Glu and Pro (EPRS1) and the auxiliary subunits AIMP1/p43, AIMP2/p38 CC and EEF1E1/p18. {ECO:0000269|PubMed:32232361}. CC -!- INTERACTION: CC Q9P2J5; P54136: RARS1; NbExp=4; IntAct=EBI-356077, EBI-355482; CC Q9P2J5; Q8N122: RPTOR; NbExp=3; IntAct=EBI-356077, EBI-1567928; CC Q9P2J5; Q9NQL2: RRAGD; NbExp=13; IntAct=EBI-356077, EBI-992949; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9P2J5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9P2J5-2; Sequence=VSP_057205; CC Name=3; CC IsoId=Q9P2J5-3; Sequence=VSP_057204; CC -!- DOMAIN: The structure of cytoplasmic leucine-tRNA ligase includes four CC main functional domains: the Rossmann-fold aminoacylation domain, the CC editing domain known as connective peptide 1 (CP1), the anticodon CC binding domain for tRNA recognition, and the vertebrate C-terminal (VC) CC domain for tRNA binding. {ECO:0000269|PubMed:32232361}. CC -!- DISEASE: Infantile liver failure syndrome 1 (ILFS1) [MIM:615438]: A CC life-threatening disorder of hepatic function that manifests with acute CC liver failure in the first few months of life. Clinical features CC include anemia, renal tubulopathy, developmental delay, seizures, CC failure to thrive, and liver steatosis and fibrosis. CC {ECO:0000269|PubMed:22607940}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the class-I aminoacyl-tRNA synthetase family. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA92590.1; 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; D84223; BAA95667.1; -; mRNA. DR EMBL; AB037773; BAA92590.1; ALT_INIT; mRNA. DR EMBL; AY513284; AAT08037.1; -; mRNA. DR EMBL; AY926480; AAX10025.1; -; mRNA. DR EMBL; AK295874; BAG58672.1; -; mRNA. DR EMBL; AC091887; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC091959; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471062; EAW61848.1; -; Genomic_DNA. DR EMBL; BC131798; AAI31799.1; -; mRNA. DR EMBL; BC150213; AAI50214.1; -; mRNA. DR EMBL; BC151214; AAI51215.1; -; mRNA. DR EMBL; BC152422; AAI52423.1; -; mRNA. DR CCDS; CCDS34265.1; -. [Q9P2J5-1] DR CCDS; CCDS83029.1; -. [Q9P2J5-2] DR RefSeq; NP_001304893.1; NM_001317964.1. DR RefSeq; NP_001304894.1; NM_001317965.1. [Q9P2J5-2] DR RefSeq; NP_057544.2; NM_016460.3. DR RefSeq; NP_064502.9; NM_020117.10. [Q9P2J5-1] DR RefSeq; XP_011535958.1; XM_011537656.2. [Q9P2J5-2] DR PDB; 2WFD; X-ray; 3.25 A; A/B=260-509. DR PDB; 6KID; X-ray; 3.15 A; A=1-1176. DR PDB; 6KIE; X-ray; 3.15 A; A=1-1061. DR PDB; 6KQY; X-ray; 3.30 A; A=1-1176. DR PDB; 6KR7; X-ray; 4.00 A; A=1-1176. DR PDB; 6LPF; X-ray; 2.49 A; A/B=1-1070. DR PDB; 6LR6; X-ray; 3.01 A; A/B=1-1070. DR PDBsum; 2WFD; -. DR PDBsum; 6KID; -. DR PDBsum; 6KIE; -. DR PDBsum; 6KQY; -. DR PDBsum; 6KR7; -. DR PDBsum; 6LPF; -. DR PDBsum; 6LR6; -. DR AlphaFoldDB; Q9P2J5; -. DR SMR; Q9P2J5; -. DR BioGRID; 119584; 350. DR ComplexPortal; CPX-2469; Multiaminoacyl-tRNA synthetase complex. DR CORUM; Q9P2J5; -. DR IntAct; Q9P2J5; 72. DR MINT; Q9P2J5; -. DR STRING; 9606.ENSP00000377954; -. DR BindingDB; Q9P2J5; -. DR ChEMBL; CHEMBL3258; -. DR DrugBank; DB00149; Leucine. DR MoonProt; Q9P2J5; -. DR GlyCosmos; Q9P2J5; 3 sites, 1 glycan. DR GlyGen; Q9P2J5; 7 sites, 1 O-linked glycan (7 sites). DR iPTMnet; Q9P2J5; -. DR MetOSite; Q9P2J5; -. DR PhosphoSitePlus; Q9P2J5; -. DR SwissPalm; Q9P2J5; -. DR BioMuta; LARS; -. DR DMDM; 48428689; -. DR EPD; Q9P2J5; -. DR jPOST; Q9P2J5; -. DR MassIVE; Q9P2J5; -. DR MaxQB; Q9P2J5; -. DR PaxDb; 9606-ENSP00000377954; -. DR PeptideAtlas; Q9P2J5; -. DR ProteomicsDB; 4339; -. DR ProteomicsDB; 83822; -. [Q9P2J5-1] DR Pumba; Q9P2J5; -. DR ABCD; Q9P2J5; 2 sequenced antibodies. DR Antibodypedia; 45640; 154 antibodies from 31 providers. DR DNASU; 51520; -. DR Ensembl; ENST00000394434.7; ENSP00000377954.2; ENSG00000133706.20. [Q9P2J5-1] DR Ensembl; ENST00000510191.5; ENSP00000426005.1; ENSG00000133706.20. [Q9P2J5-2] DR Ensembl; ENST00000674174.1; ENSP00000501434.1; ENSG00000133706.20. [Q9P2J5-2] DR GeneID; 51520; -. DR KEGG; hsa:51520; -. DR MANE-Select; ENST00000394434.7; ENSP00000377954.2; NM_020117.11; NP_064502.9. DR UCSC; uc003lnx.2; human. [Q9P2J5-1] DR AGR; HGNC:6512; -. DR CTD; 51520; -. DR DisGeNET; 51520; -. DR GeneCards; LARS1; -. DR HGNC; HGNC:6512; LARS1. DR HPA; ENSG00000133706; Low tissue specificity. DR MalaCards; LARS1; -. DR MIM; 151350; gene. DR MIM; 615438; phenotype. DR neXtProt; NX_Q9P2J5; -. DR OpenTargets; ENSG00000133706; -. DR Orphanet; 370088; Acute infantile liver failure-multisystemic involvement syndrome. DR PharmGKB; PA30297; -. DR VEuPathDB; HostDB:ENSG00000133706; -. DR eggNOG; KOG0437; Eukaryota. DR GeneTree; ENSGT00390000012163; -. DR HOGENOM; CLU_004174_2_1_1; -. DR InParanoid; Q9P2J5; -. DR OMA; KFIEWQF; -. DR OrthoDB; 5472610at2759; -. DR PhylomeDB; Q9P2J5; -. DR TreeFam; TF105718; -. DR BRENDA; 6.1.1.4; 2681. DR PathwayCommons; Q9P2J5; -. DR Reactome; R-HSA-2408522; Selenoamino acid metabolism. DR Reactome; R-HSA-379716; Cytosolic tRNA aminoacylation. DR SABIO-RK; Q9P2J5; -. DR SignaLink; Q9P2J5; -. DR SIGNOR; Q9P2J5; -. DR BioGRID-ORCS; 51520; 807 hits in 1159 CRISPR screens. DR ChiTaRS; LARS; human. DR EvolutionaryTrace; Q9P2J5; -. DR GeneWiki; Leucyl-tRNA_synthetase; -. DR GenomeRNAi; 51520; -. DR Pharos; Q9P2J5; Tchem. DR PRO; PR:Q9P2J5; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q9P2J5; Protein. DR Bgee; ENSG00000133706; Expressed in Brodmann (1909) area 23 and 211 other cell types or tissues. DR ExpressionAtlas; Q9P2J5; baseline and differential. DR GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:CAFA. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0012505; C:endomembrane system; IDA:CAFA. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:CAFA. DR GO; GO:0005764; C:lysosome; IMP:CAFA. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0002161; F:aminoacyl-tRNA editing activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004819; F:glutamine-tRNA ligase activity; IDA:UniProtKB. DR GO; GO:0005096; F:GTPase activator activity; IMP:CAFA. DR GO; GO:0004823; F:leucine-tRNA ligase activity; IDA:UniProtKB. DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:CAFA. DR GO; GO:0071230; P:cellular response to amino acid stimulus; IMP:CAFA. DR GO; GO:0071233; P:cellular response to leucine; IMP:CAFA. DR GO; GO:1990253; P:cellular response to leucine starvation; IMP:CAFA. DR GO; GO:0006425; P:glutaminyl-tRNA aminoacylation; IDA:UniProtKB. DR GO; GO:0006429; P:leucyl-tRNA aminoacylation; IDA:UniProtKB. DR GO; GO:0043547; P:positive regulation of GTPase activity; IMP:CAFA. DR GO; GO:0032008; P:positive regulation of TOR signaling; IMP:CAFA. DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IMP:CAFA. DR GO; GO:0008361; P:regulation of cell size; IMP:CAFA. DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome. DR CDD; cd07959; Anticodon_Ia_Leu_AEc; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR Gene3D; 3.90.740.10; Valyl/Leucyl/Isoleucyl-tRNA synthetase, editing domain; 1. DR InterPro; IPR001412; aa-tRNA-synth_I_CS. DR InterPro; IPR002300; aa-tRNA-synth_Ia. DR InterPro; IPR004493; Leu-tRNA-synth_Ia_arc/euk. DR InterPro; IPR013155; M/V/L/I-tRNA-synth_anticd-bd. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR InterPro; IPR009080; tRNAsynth_Ia_anticodon-bd. DR InterPro; IPR009008; Val/Leu/Ile-tRNA-synth_edit. DR NCBIfam; TIGR00395; leuS_arch; 1. DR PANTHER; PTHR45794:SF1; LEUCINE--TRNA LIGASE, CYTOPLASMIC; 1. DR PANTHER; PTHR45794; LEUCYL-TRNA SYNTHETASE; 1. DR Pfam; PF08264; Anticodon_1; 1. DR Pfam; PF00133; tRNA-synt_1; 2. DR SUPFAM; SSF47323; Anticodon-binding domain of a subclass of class I aminoacyl-tRNA synthetases; 1. DR SUPFAM; SSF52374; Nucleotidylyl transferase; 1. DR SUPFAM; SSF50677; ValRS/IleRS/LeuRS editing domain; 1. DR PROSITE; PS00178; AA_TRNA_LIGASE_I; 1. DR Genevisible; Q9P2J5; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Aminoacyl-tRNA synthetase; KW ATP-binding; Cytoplasm; Disease variant; Ligase; Nucleotide-binding; KW Phosphoprotein; Protein biosynthesis; Reference proteome. FT CHAIN 1..1176 FT /note="Leucine--tRNA ligase, cytoplasmic" FT /id="PRO_0000152150" FT REGION 260..509 FT /note="Editing domain" FT /evidence="ECO:0000305|PubMed:19426743" FT MOTIF 60..63 FT /note="'HIGH' region" FT /evidence="ECO:0000305|PubMed:32232361, FT ECO:0007744|PDB:6LPF" FT MOTIF 716..720 FT /note="'KMSKS' region" FT /evidence="ECO:0000305|PubMed:32232361, FT ECO:0007744|PDB:6LPF" FT BINDING 52 FT /ligand="L-leucine" FT /ligand_id="ChEBI:CHEBI:57427" FT /evidence="ECO:0000305|PubMed:32232361, FT ECO:0007744|PDB:6LPF" FT BINDING 54 FT /ligand="L-leucine" FT /ligand_id="ChEBI:CHEBI:57427" FT /evidence="ECO:0000305|PubMed:32232361, FT ECO:0007744|PDB:6LPF" FT BINDING 594 FT /ligand="L-leucine" FT /ligand_id="ChEBI:CHEBI:57427" FT /evidence="ECO:0000305|PubMed:32232361, FT ECO:0007744|PDB:6LPF" FT BINDING 597 FT /ligand="L-leucine" FT /ligand_id="ChEBI:CHEBI:57427" FT /evidence="ECO:0000305|PubMed:32232361, FT ECO:0007744|PDB:6LPF" FT BINDING 719 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000250" FT MOD_RES 167 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 720 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 970 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q8BMJ2" FT MOD_RES 1047 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:Q8BMJ2" FT VAR_SEQ 1..691 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_057204" FT VAR_SEQ 1..54 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_057205" FT VARIANT 82 FT /note="K -> R (in dbSNP:rs112954500)" FT /evidence="ECO:0000269|PubMed:22607940" FT /id="VAR_070437" FT VARIANT 373 FT /note="Y -> C (in ILFS1; dbSNP:rs201861847)" FT /evidence="ECO:0000269|PubMed:22607940" FT /id="VAR_070438" FT VARIANT 1088 FT /note="R -> K (in dbSNP:rs10988)" FT /evidence="ECO:0000269|Ref.1" FT /id="VAR_052637" FT MUTAGEN 236..256 FT /note="Missing: Loss of leucyl-tRNA ligase activity. FT Decreased activity in post-transfer editing of tRNA(Leu) FT mischarged with methionine." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 242 FT /note="P->E: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 245 FT /note="G->A: No effect on leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 245 FT /note="G->D,R: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 245 FT /note="G->P: Loss of leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 247 FT /note="P->A: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 250 FT /note="D->A: Reduced leucyl-tRNA ligase activity. Decreased FT activity in pre-transfer editing and no effect on FT post-transfer editing of tRNA(Leu) mischarged with FT methionine." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 250 FT /note="D->E: No effect on leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 250 FT /note="D->N: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 250 FT /note="D->R: Loss of leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 514..534 FT /note="Missing: Loss of leucyl-tRNA ligase activity. FT Decreased activity in post-transfer editing of tRNA(Leu) FT mischarged with methionine." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 519 FT /note="S->G: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 523 FT /note="V->I: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 525 FT /note="A->S: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT MUTAGEN 527 FT /note="C->E: Reduced leucyl-tRNA ligase activity." FT /evidence="ECO:0000269|PubMed:25051973" FT CONFLICT 271 FT /note="V -> A (in Ref. 1; BAA95667)" FT /evidence="ECO:0000305" FT CONFLICT 892 FT /note="N -> D (in Ref. 1; BAA95667)" FT /evidence="ECO:0000305" FT CONFLICT 1026 FT /note="Y -> C (in Ref. 7; AAI31799)" FT /evidence="ECO:0000305" FT HELIX 8..27 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 28..30 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 34..37 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 45..49 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 56..58 FT /evidence="ECO:0007829|PDB:6KID" FT HELIX 61..79 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 83..85 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 89..91 FT /evidence="ECO:0007829|PDB:6KIE" FT STRAND 93..95 FT /evidence="ECO:0007829|PDB:6KIE" FT HELIX 96..110 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 112..115 FT /evidence="ECO:0007829|PDB:6KID" FT HELIX 157..163 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 168..171 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 172..175 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 177..195 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 201..203 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 212..227 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 231..241 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 242..245 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 250..252 FT /evidence="ECO:0007829|PDB:6KID" FT STRAND 253..255 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 261..271 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 277..282 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 287..294 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 296..301 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 304..307 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 311..317 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 319..321 FT /evidence="ECO:0007829|PDB:6KID" FT STRAND 323..326 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 328..336 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 340..342 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 348..353 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 354..357 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 361..363 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 368..370 FT /evidence="ECO:0007829|PDB:2WFD" FT STRAND 372..376 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 382..384 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 387..391 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 393..395 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 397..408 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 410..415 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 420..422 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 423..425 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 435..437 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 438..440 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 441..448 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 457..466 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 467..469 FT /evidence="ECO:0007829|PDB:6KQY" FT TURN 470..472 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 479..482 FT /evidence="ECO:0007829|PDB:6KIE" FT HELIX 487..489 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 491..500 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 503..512 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 516..519 FT /evidence="ECO:0007829|PDB:6KQY" FT STRAND 523..533 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 537..549 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 550..554 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 555..567 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 570..572 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 574..580 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 593..595 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 596..599 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 601..610 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 611..613 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 627..629 FT /evidence="ECO:0007829|PDB:6KID" FT HELIX 632..639 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 640..643 FT /evidence="ECO:0007829|PDB:6KQY" FT HELIX 652..665 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 670..674 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 675..677 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 678..680 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 681..692 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 693..695 FT /evidence="ECO:0007829|PDB:6KID" FT HELIX 697..699 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 703..707 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 710..712 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 719..721 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 727..744 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 748..751 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 753..755 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 757..779 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 781..783 FT /evidence="ECO:0007829|PDB:6LR6" FT HELIX 792..813 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 817..824 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 826..838 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 845..859 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 860..862 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 864..873 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 880..882 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 893..912 FT /evidence="ECO:0007829|PDB:6LPF" FT TURN 913..915 FT /evidence="ECO:0007829|PDB:6KQY" FT STRAND 935..939 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 946..961 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 962..964 FT /evidence="ECO:0007829|PDB:6KQY" FT HELIX 969..977 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 980..985 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 986..1003 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 1004..1008 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 1009..1011 FT /evidence="ECO:0007829|PDB:6KIE" FT HELIX 1016..1021 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 1024..1031 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 1034..1039 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 1041..1044 FT /evidence="ECO:0007829|PDB:6LPF" FT HELIX 1046..1051 FT /evidence="ECO:0007829|PDB:6LPF" FT STRAND 1058..1060 FT /evidence="ECO:0007829|PDB:6LPF" SQ SEQUENCE 1176 AA; 134466 MW; 44A4D1A1EF31634A CRC64; MAERKGTAKV DFLKKIEKEI QQKWDTERVF EVNASNLEKQ TSKGKYFVTF PYPYMNGRLH LGHTFSLSKC EFAVGYQRLK GKCCLFPFGL HCTGMPIKAC ADKLKREIEL YGCPPDFPDE EEEEEETSVK TEDIIIKDKA KGKKSKAAAK AGSSKYQWGI MKSLGLSDEE IVKFSEAEHW LDYFPPLAIQ DLKRMGLKVD WRRSFITTDV NPYYDSFVRW QFLTLRERNK IKFGKRYTIY SPKDGQPCMD HDRQTGEGVG PQEYTLLKLK VLEPYPSKLS GLKGKNIFLV AATLRPETMF GQTNCWVRPD MKYIGFETVN GDIFICTQKA ARNMSYQGFT KDNGVVPVVK ELMGEEILGA SLSAPLTSYK VIYVLPMLTI KEDKGTGVVT SVPSDSPDDI AALRDLKKKQ ALRAKYGIRD DMVLPFEPVP VIEIPGFGNL SAVTICDELK IQSQNDREKL AEAKEKIYLK GFYEGIMLVD GFKGQKVQDV KKTIQKKMID AGDALIYMEP EKQVMSRSSD ECVVALCDQW YLDYGEENWK KQTSQCLKNL ETFCEETRRN FEATLGWLQE HACSRTYGLG THLPWDEQWL IESLSDSTIY MAFYTVAHLL QGGNLHGQAE SPLGIRPQQM TKEVWDYVFF KEAPFPKTQI AKEKLDQLKQ EFEFWYPVDL RVSGKDLVPN HLSYYLYNHV AMWPEQSDKW PTAVRANGHL LLNSEKMSKS TGNFLTLTQA IDKFSADGMR LALADAGDTV EDANFVEAMA DAGILRLYTW VEWVKEMVAN WDSLRSGPAS TFNDRVFASE LNAGIIKTDQ NYEKMMFKEA LKTGFFEFQA AKDKYRELAV EGMHRELVFR FIEVQTLLLA PFCPHLCEHI WTLLGKPDSI MNASWPVAGP VNEVLIHSSQ YLMEVTHDLR LRLKNYMMPA KGKKTDKQPL QKPSHCTIYV AKNYPPWQHT TLSVLRKHFE ANNGKLPDNK VIASELGSMP ELKKYMKKVM PFVAMIKENL EKMGPRILDL QLEFDEKAVL MENIVYLTNS LELEHIEVKF ASEAEDKIRE DCCPGKPLNV FRIEPGVSVS LVNPQPSNGH FSTKIEIRQG DNCDSIIRRL MKMNRGIKDL SKVKLMRFDD PLLGPRRVPV LGKEYTEKTP ISEHAVFNVD LMSKKIHLTE NGIRVDIGDT IIYLVH //