ID   SYLM_HUMAN              Reviewed;         903 AA.
AC   Q15031;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1997, sequence version 2.
DT   27-MAR-2024, entry version 198.
DE   RecName: Full=Leucine--tRNA ligase, mitochondrial {ECO:0000305};
DE            EC=6.1.1.4 {ECO:0000269|PubMed:26537577};
DE   AltName: Full=Leucyl-tRNA synthetase;
DE            Short=LeuRS;
DE   Flags: Precursor;
GN   Name=LARS2 {ECO:0000312|HGNC:HGNC:17095}; Synonyms=KIAA0028;
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 [LARGE SCALE MRNA].
RC   TISSUE=Bone marrow;
RX   PubMed=7584026; DOI=10.1093/dnares/1.1.27;
RA   Nomura N., Miyajima N., Sazuka T., Tanaka A., Kawarabayasi Y., Sato S.,
RA   Nagase T., Seki N., Ishikawa K., Tabata S.;
RT   "Prediction of the coding sequences of unidentified human genes. I. The
RT   coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of
RT   randomly sampled cDNA clones from human immature myeloid cell line KG-1.";
RL   DNA Res. 1:27-35(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Testis;
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   [3]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-236, AND IDENTIFICATION BY MASS
RP   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   [4]
RP   TISSUE SPECIFICITY.
RX   PubMed=20194621; DOI=10.1128/mcb.01614-09;
RA   Li R., Guan M.X.;
RT   "Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial
RT   dysfunctions due to the tRNALeu(UUR) A3243G mutation, associated with
RT   mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms
RT   and diabetes.";
RL   Mol. Cell. Biol. 30:2147-2154(2010).
RN   [5]
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   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-711, AND IDENTIFICATION BY
RP   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   [7]
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   [8]
RP   VARIANTS PRLTS4 ASN-522 AND MET-629, AND CHARACTERIZATION OF VARIANTS
RP   PRLTS4 ASN-522 AND MET-629.
RX   PubMed=23541342; DOI=10.1016/j.ajhg.2013.03.007;
RA   Pierce S.B., Gersak K., Michaelson-Cohen R., Walsh T., Lee M.K., Malach D.,
RA   Klevit R.E., King M.C., Levy-Lahad E.;
RT   "Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to
RT   premature ovarian failure and hearing loss in Perrault syndrome.";
RL   Am. J. Hum. Genet. 92:614-620(2013).
RN   [9]
RP   INVOLVEMENT IN HLASA, VARIANTS HLASA VAL-430 AND ASN-522, CHARACTERIZATION
RP   OF VARIANT HLASA VAL-430 AND ASN-522, FUNCTION, CATALYTIC ACTIVITY, AND
RP   BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=26537577; DOI=10.1007/8904_2015_515;
RA   Riley L.G., Rudinger-Thirion J., Schmitz-Abe K., Thorburn D.R., Davis R.L.,
RA   Teo J., Arbuckle S., Cooper S.T., Campagna D.R., Frugier M., Markianos K.,
RA   Sue C.M., Fleming M.D., Christodoulou J.;
RT   "LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic
RT   Anemia, and Multisystem Failure.";
RL   JIMD Rep. 28:49-57(2016).
CC   -!- FUNCTION: Catalyzes the attachment of leucine to its cognate tRNA.
CC       {ECO:0000269|PubMed:26537577}.
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:26537577};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=1.35 uM for L-leucine {ECO:0000269|PubMed:26537577};
CC   -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Ubiquitously expressed, but highest expression in
CC       tissues with high metabolic rates, such as skeletal muscle, heart, and
CC       kidney. {ECO:0000269|PubMed:20194621}.
CC   -!- DISEASE: Perrault syndrome 4 (PRLTS4) [MIM:615300]: An autosomal
CC       recessive, sex-influenced disorder characterized by sensorineural
CC       deafness in both males and females, and ovarian dysgenesis in females.
CC       Affected females have primary amenorrhea, streak gonads, and
CC       infertility, whereas affected males show normal pubertal development
CC       and are fertile. {ECO:0000269|PubMed:23541342}. Note=The disease is
CC       caused by variants affecting the gene represented in this entry.
CC   -!- DISEASE: Hydrops, lactic acidosis, and sideroblastic anemia (HLASA)
CC       [MIM:617021]: A lethal, multisystem metabolic disorder characterized by
CC       severe lactic acidosis, hydrops, and sideroblastic anemia. Additional
CC       features include impaired cardiac function, disordered coagulation,
CC       pulmonary hypertension, and progressive renal disease.
CC       {ECO:0000269|PubMed:26537577}. 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=BAA04877.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; D21851; BAA04877.2; ALT_INIT; mRNA.
DR   EMBL; BC025989; AAH25989.1; -; mRNA.
DR   CCDS; CCDS2728.1; -.
DR   RefSeq; NP_056155.1; NM_015340.3.
DR   RefSeq; XP_005265063.1; XM_005265006.1.
DR   AlphaFoldDB; Q15031; -.
DR   SMR; Q15031; -.
DR   BioGRID; 116968; 174.
DR   IntAct; Q15031; 25.
DR   MINT; Q15031; -.
DR   STRING; 9606.ENSP00000498867; -.
DR   BindingDB; Q15031; -.
DR   ChEMBL; CHEMBL4105806; -.
DR   DrugBank; DB00149; Leucine.
DR   GlyGen; Q15031; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q15031; -.
DR   PhosphoSitePlus; Q15031; -.
DR   SwissPalm; Q15031; -.
DR   BioMuta; LARS2; -.
DR   DMDM; 2501029; -.
DR   EPD; Q15031; -.
DR   jPOST; Q15031; -.
DR   MassIVE; Q15031; -.
DR   MaxQB; Q15031; -.
DR   PaxDb; 9606-ENSP00000408576; -.
DR   PeptideAtlas; Q15031; -.
DR   ProteomicsDB; 60380; -.
DR   Pumba; Q15031; -.
DR   Antibodypedia; 29557; 188 antibodies from 25 providers.
DR   DNASU; 23395; -.
DR   Ensembl; ENST00000642274.1; ENSP00000495707.1; ENSG00000011376.12.
DR   Ensembl; ENST00000645846.2; ENSP00000495093.1; ENSG00000011376.12.
DR   Ensembl; ENST00000650792.2; ENSP00000498867.1; ENSG00000011376.12.
DR   GeneID; 23395; -.
DR   KEGG; hsa:23395; -.
DR   MANE-Select; ENST00000645846.2; ENSP00000495093.1; NM_015340.4; NP_056155.1.
DR   UCSC; uc003cop.2; human.
DR   AGR; HGNC:17095; -.
DR   CTD; 23395; -.
DR   DisGeNET; 23395; -.
DR   GeneCards; LARS2; -.
DR   GeneReviews; LARS2; -.
DR   HGNC; HGNC:17095; LARS2.
DR   HPA; ENSG00000011376; Low tissue specificity.
DR   MalaCards; LARS2; -.
DR   MIM; 604544; gene.
DR   MIM; 615300; phenotype.
DR   MIM; 617021; phenotype.
DR   neXtProt; NX_Q15031; -.
DR   OpenTargets; ENSG00000011376; -.
DR   Orphanet; 528091; Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome.
DR   Orphanet; 642945; Perrault syndrome type 1.
DR   Orphanet; 642976; Perrault syndrome type 2.
DR   PharmGKB; PA134982982; -.
DR   VEuPathDB; HostDB:ENSG00000011376; -.
DR   eggNOG; KOG0435; Eukaryota.
DR   GeneTree; ENSGT00390000015114; -.
DR   HOGENOM; CLU_004427_0_1_1; -.
DR   InParanoid; Q15031; -.
DR   OMA; TFMVLAP; -.
DR   OrthoDB; 2876972at2759; -.
DR   PhylomeDB; Q15031; -.
DR   TreeFam; TF105662; -.
DR   BRENDA; 6.1.1.4; 2681.
DR   PathwayCommons; Q15031; -.
DR   Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation.
DR   SABIO-RK; Q15031; -.
DR   SignaLink; Q15031; -.
DR   SIGNOR; Q15031; -.
DR   BioGRID-ORCS; 23395; 397 hits in 1172 CRISPR screens.
DR   ChiTaRS; LARS2; human.
DR   GeneWiki; LARS2; -.
DR   GenomeRNAi; 23395; -.
DR   Pharos; Q15031; Tbio.
DR   PRO; PR:Q15031; -.
DR   Proteomes; UP000005640; Chromosome 3.
DR   RNAct; Q15031; Protein.
DR   Bgee; ENSG00000011376; Expressed in ventricular zone and 205 other cell types or tissues.
DR   ExpressionAtlas; Q15031; baseline and differential.
DR   GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR   GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR   GO; GO:0002161; F:aminoacyl-tRNA editing activity; IEA:InterPro.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004823; F:leucine-tRNA ligase activity; IDA:UniProtKB.
DR   GO; GO:0006429; P:leucyl-tRNA aminoacylation; IDA:HGNC.
DR   GO; GO:0032543; P:mitochondrial translation; IBA:GO_Central.
DR   GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome.
DR   CDD; cd07958; Anticodon_Ia_Leu_BEm; 1.
DR   CDD; cd00812; LeuRS_core; 1.
DR   Gene3D; 3.40.50.620; HUPs; 2.
DR   InterPro; IPR001412; aa-tRNA-synth_I_CS.
DR   InterPro; IPR002300; aa-tRNA-synth_Ia.
DR   InterPro; IPR002302; Leu-tRNA-ligase.
DR   InterPro; IPR025709; Leu_tRNA-synth_edit.
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; TIGR00396; leuS_bact; 1.
DR   PANTHER; PTHR43740:SF3; LEUCINE--TRNA LIGASE, MITOCHONDRIAL; 1.
DR   PANTHER; PTHR43740; LEUCYL-TRNA SYNTHETASE; 1.
DR   Pfam; PF08264; Anticodon_1; 1.
DR   Pfam; PF00133; tRNA-synt_1; 3.
DR   Pfam; PF13603; tRNA-synt_1_2; 1.
DR   PRINTS; PR00985; TRNASYNTHLEU.
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; Q15031; HS.
PE   1: Evidence at protein level;
KW   Acetylation; Aminoacyl-tRNA synthetase; ATP-binding; Deafness;
KW   Disease variant; Ligase; Mitochondrion; Nucleotide-binding; Phosphoprotein;
KW   Protein biosynthesis; Reference proteome; Transit peptide.
FT   TRANSIT         1..?
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           ?..903
FT                   /note="Leucine--tRNA ligase, mitochondrial"
FT                   /id="PRO_0000035806"
FT   MOTIF           92..102
FT                   /note="'HIGH' region"
FT   MOTIF           639..643
FT                   /note="'KMSKS' region"
FT   BINDING         642
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         68
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VDC0"
FT   MOD_RES         236
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:19608861"
FT   MOD_RES         711
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:23186163"
FT   VARIANT         430
FT                   /note="A -> V (in HLASA; decreased leucine-tRNA ligase
FT                   activity; dbSNP:rs879255606)"
FT                   /evidence="ECO:0000269|PubMed:26537577"
FT                   /id="VAR_076997"
FT   VARIANT         522
FT                   /note="T -> N (in PRLTS4 and HLASA; reduced activity;
FT                   decreased leucine-tRNA ligase activity; dbSNP:rs199589947)"
FT                   /evidence="ECO:0000269|PubMed:23541342,
FT                   ECO:0000269|PubMed:26537577"
FT                   /id="VAR_070094"
FT   VARIANT         629
FT                   /note="T -> M (in PRLTS4; uncertain significance; the
FT                   mutant is functional in a yeast complementation assay;
FT                   dbSNP:rs398123036)"
FT                   /evidence="ECO:0000269|PubMed:23541342"
FT                   /id="VAR_070095"
FT   VARIANT         727
FT                   /note="K -> N (in dbSNP:rs36054230)"
FT                   /id="VAR_052638"
FT   VARIANT         831
FT                   /note="E -> D (in dbSNP:rs9827689)"
FT                   /id="VAR_052639"
SQ   SEQUENCE   903 AA;  101976 MW;  D9AC143125124F58 CRC64;
     MASVWQRLGF YASLLKRQLN GGPDVIKWER RVIPGCTRSI YSATGKWTKE YTLQTRKDVE
     KWWHQRIKEQ ASKISEADKS KPKFYVLSMF PYPSGKLHMG HVRVYTISDT IARFQKMRGM
     QVINPMGWDA FGLPAENAAV ERNLHPQSWT QSNIKHMRKQ LDRLGLCFSW DREITTCLPD
     YYKWTQYLFI KLYEAGLAYQ KEALVNWDPV DQTVLANEQV DEHGCSWRSG AKVEQKYLRQ
     WFIKTTAYAK AMQDALADLP EWYGIKGMQA HWIGDCVGCH LDFTLKVHGQ ATGEKLTAYT
     ATPEAIYGTS HVAISPSHRL LHGHSSLKEA LRMALVPGKD CLTPVMAVNM LTQQEVPVVI
     LAKADLEGSL DSKIGIPSTS SEDTILAQTL GLAYSEVIET LPDGTERLSS SAEFTGMTRQ
     DAFLALTQKA RGKRVGGDVT SDKLKDWLIS RQRYWGTPIP IVHCPVCGPT PVPLEDLPVT
     LPNIASFTGK GGPPLAMASE WVNCSCPRCK GAAKRETDTM DTFVDSAWYY FRYTDPHNPH
     SPFNTAVADY WMPVDLYIGG KEHAVMHLFY ARFFSHFCHD QKMVKHREPF HKLLAQGLIK
     GQTFRLPSGQ YLQREEVDLT GSVPVHAKTK EKLEVTWEKM SKSKHNGVDP EEVVEQYGID
     TIRLYILFAA PPEKDILWDV KTDALPGVLR WQQRLWTLTT RFIEARASGK SPQPQLLSNK
     EKAEARKLWE YKNSVISQVT THFTEDFSLN SAISQLMGLS NALSQASQSV ILHSPEFEDA
     LCALMVMAAP LAPHVTSEIW AGLALVPRKL CAHYTWDASV LLQAWPAVDP EFLQQPEVVQ
     MAVLINNKAC GKIPVPQQVA RDQDKVHEFV LQSELGVRLL QGRSIKKSFL SPRTALINFL
     VQD
//