SYLM_HUMAN
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 03-AUG-2022, entry version 189.
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; 163.
DR IntAct; Q15031; 24.
DR MINT; Q15031; -.
DR STRING; 9606.ENSP00000408576; -.
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 BioMuta; LARS2; -.
DR DMDM; 2501029; -.
DR EPD; Q15031; -.
DR jPOST; Q15031; -.
DR MassIVE; Q15031; -.
DR MaxQB; Q15031; -.
DR PaxDb; Q15031; -.
DR PeptideAtlas; Q15031; -.
DR PRIDE; Q15031; -.
DR ProteomicsDB; 60380; -.
DR Antibodypedia; 29557; 172 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 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; 2855; Perrault syndrome.
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; 375759at2759; -.
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 BioGRID-ORCS; 23395; 364 hits in 1093 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 203 other tissues.
DR ExpressionAtlas; Q15031; baseline and differential.
DR Genevisible; Q15031; HS.
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 Gene3D; 3.40.50.620; -; 2.
DR InterPro; IPR001412; aa-tRNA-synth_I_CS.
DR InterPro; IPR002300; aa-tRNA-synth_Ia.
DR InterPro; IPR002302; Leu-tRNA-ligase.
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 PANTHER; PTHR43740; PTHR43740; 1.
DR Pfam; PF08264; Anticodon_1; 1.
DR Pfam; PF00133; tRNA-synt_1; 3.
DR PRINTS; PR00985; TRNASYNTHLEU.
DR SUPFAM; SSF47323; SSF47323; 1.
DR SUPFAM; SSF50677; SSF50677; 1.
DR TIGRFAMs; TIGR00396; leuS_bact; 1.
DR PROSITE; PS00178; AA_TRNA_LIGASE_I; 1.
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; unknown pathological
FT significance; the mutant is functional in a yeast
FT complementation assay; 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
