ID   SYLC_MOUSE              Reviewed;        1178 AA.
AC   Q8BMJ2; Q8BKW9;
DT   07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT   07-JUN-2004, sequence version 2.
DT   24-JAN-2024, entry version 157.
DE   RecName: Full=Leucine--tRNA ligase, cytoplasmic {ECO:0000250|UniProtKB:Q9P2J5};
DE            EC=6.1.1.4 {ECO:0000250|UniProtKB:Q9P2J5};
DE   AltName: Full=Leucyl-tRNA synthetase {ECO:0000250|UniProtKB:Q9P2J5};
DE            Short=LeuRS {ECO:0000250|UniProtKB:Q9P2J5};
GN   Name=Lars1; Synonyms=Lars;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [2]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung,
RC   Pancreas, Spleen, and Testis;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [3]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-972 AND LYS-1049, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Embryonic fibroblast;
RX   PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA   Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA   Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT   "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT   pathways.";
RL   Mol. Cell 50:919-930(2013).
CC   -!- FUNCTION: Aminoacyl-tRNA synthetase that catalyzes the specific
CC       attachment of leucine to its cognate tRNA (tRNA(Leu)). It performs tRNA
CC       aminoacylation in a two-step reaction: Leu is initially activated by
CC       ATP to form a leucyl-adenylate (Leu-AMP) intermediate; then the leucyl
CC       moiety is transferred to the acceptor 3' end of the tRNA to yield
CC       leucyl-tRNA. To improve the fidelity of catalytic reactions, it is also
CC       able to hydrolyze misactivated aminoacyl-adenylate intermediates (pre-
CC       transfer editing) and mischarged aminoacyl-tRNAs (post-transfer
CC       editing). {ECO:0000250|UniProtKB:Q9P2J5}.
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:0000250|UniProtKB:Q9P2J5};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11689;
CC         Evidence={ECO:0000250|UniProtKB:Q9P2J5};
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:0000250|UniProtKB:Q9P2J5};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77536;
CC         Evidence={ECO:0000250|UniProtKB:Q9P2J5};
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. {ECO:0000250|UniProtKB:Q9P2J5}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
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:0000250|UniProtKB:Q9P2J5}.
CC   -!- SIMILARITY: Belongs to the class-I aminoacyl-tRNA synthetase family.
CC       {ECO:0000305}.
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DR   EMBL; AK030778; BAC27133.1; -; mRNA.
DR   EMBL; AK049472; BAC33766.1; -; mRNA.
DR   CCDS; CCDS37796.1; -.
DR   RefSeq; NP_598898.2; NM_134137.2.
DR   AlphaFoldDB; Q8BMJ2; -.
DR   SMR; Q8BMJ2; -.
DR   BioGRID; 223191; 32.
DR   IntAct; Q8BMJ2; 2.
DR   STRING; 10090.ENSMUSP00000095197; -.
DR   GlyGen; Q8BMJ2; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q8BMJ2; -.
DR   PhosphoSitePlus; Q8BMJ2; -.
DR   SwissPalm; Q8BMJ2; -.
DR   EPD; Q8BMJ2; -.
DR   jPOST; Q8BMJ2; -.
DR   MaxQB; Q8BMJ2; -.
DR   PaxDb; 10090-ENSMUSP00000095197; -.
DR   ProteomicsDB; 253439; -.
DR   Pumba; Q8BMJ2; -.
DR   Antibodypedia; 45640; 154 antibodies from 31 providers.
DR   DNASU; 107045; -.
DR   Ensembl; ENSMUST00000097590.5; ENSMUSP00000095197.4; ENSMUSG00000024493.10.
DR   GeneID; 107045; -.
DR   KEGG; mmu:107045; -.
DR   UCSC; uc008etp.1; mouse.
DR   AGR; MGI:1913808; -.
DR   CTD; 51520; -.
DR   MGI; MGI:1913808; Lars1.
DR   VEuPathDB; HostDB:ENSMUSG00000024493; -.
DR   eggNOG; KOG0437; Eukaryota.
DR   GeneTree; ENSGT00390000012163; -.
DR   HOGENOM; CLU_004174_1_0_1; -.
DR   InParanoid; Q8BMJ2; -.
DR   OMA; KFIEWQF; -.
DR   OrthoDB; 5472610at2759; -.
DR   PhylomeDB; Q8BMJ2; -.
DR   TreeFam; TF105718; -.
DR   BioGRID-ORCS; 107045; 32 hits in 116 CRISPR screens.
DR   ChiTaRS; Lars; mouse.
DR   PRO; PR:Q8BMJ2; -.
DR   Proteomes; UP000000589; Chromosome 18.
DR   RNAct; Q8BMJ2; Protein.
DR   Bgee; ENSMUSG00000024493; Expressed in floor plate of midbrain and 294 other cell types or tissues.
DR   ExpressionAtlas; Q8BMJ2; baseline and differential.
DR   GO; GO:0017101; C:aminoacyl-tRNA synthetase multienzyme complex; IDA:CAFA.
DR   GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0012505; C:endomembrane system; ISO:MGI.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR   GO; GO:0005764; C:lysosome; ISO:MGI.
DR   GO; GO:0016604; C:nuclear body; ISO:MGI.
DR   GO; GO:0002161; F:aminoacyl-tRNA editing activity; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004819; F:glutamine-tRNA ligase activity; ISO:MGI.
DR   GO; GO:0005096; F:GTPase activator activity; ISO:MGI.
DR   GO; GO:0004823; F:leucine-tRNA ligase activity; IMP:CAFA.
DR   GO; GO:0034198; P:cellular response to amino acid starvation; ISO:MGI.
DR   GO; GO:0071230; P:cellular response to amino acid stimulus; ISO:MGI.
DR   GO; GO:0071233; P:cellular response to leucine; ISO:MGI.
DR   GO; GO:1990253; P:cellular response to leucine starvation; ISO:MGI.
DR   GO; GO:0006425; P:glutaminyl-tRNA aminoacylation; ISO:MGI.
DR   GO; GO:0006429; P:leucyl-tRNA aminoacylation; IDA:CAFA.
DR   GO; GO:0032008; P:positive regulation of TOR signaling; ISO:MGI.
DR   GO; GO:1904263; P:positive regulation of TORC1 signaling; ISO:MGI.
DR   GO; GO:0008361; P:regulation of cell size; ISO:MGI.
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; Q8BMJ2; MM.
PE   1: Evidence at protein level;
KW   Acetylation; Aminoacyl-tRNA synthetase; ATP-binding; Cytoplasm; Ligase;
KW   Nucleotide-binding; Phosphoprotein; Protein biosynthesis;
KW   Reference proteome.
FT   CHAIN           1..1178
FT                   /note="Leucine--tRNA ligase, cytoplasmic"
FT                   /id="PRO_0000152151"
FT   REGION          262..511
FT                   /note="Editing domain"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   MOTIF           62..65
FT                   /note="'HIGH' region"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   MOTIF           718..722
FT                   /note="'KMSKS' region"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   BINDING         54
FT                   /ligand="L-leucine"
FT                   /ligand_id="ChEBI:CHEBI:57427"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   BINDING         56
FT                   /ligand="L-leucine"
FT                   /ligand_id="ChEBI:CHEBI:57427"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   BINDING         596
FT                   /ligand="L-leucine"
FT                   /ligand_id="ChEBI:CHEBI:57427"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   BINDING         599
FT                   /ligand="L-leucine"
FT                   /ligand_id="ChEBI:CHEBI:57427"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   BINDING         721
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   MOD_RES         169
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   MOD_RES         722
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9P2J5"
FT   MOD_RES         972
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:23806337"
FT   MOD_RES         1049
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0007744|PubMed:23806337"
FT   CONFLICT        218
FT                   /note="S -> P (in Ref. 1; BAC33766)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        869
FT                   /note="C -> S (in Ref. 1; BAC33766)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        954
FT                   /note="L -> Q (in Ref. 1; BAC27133)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        1127
FT                   /note="P -> H (in Ref. 1; BAC27133)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   1178 AA;  134192 MW;  1186583D5237FFC1 CRC64;
     MAGRKGTAKV DFLKEIEKEA QQKWEAEKVF EVSASRLEKQ KQSSKGKYFV TFPYPYMNGR
     LHLGHTFSLS KCEFAVGYQR LKGKSCLFPF GLHCTGMPIK ACADKLKREI ELYGCPPDFP
     EEEEEEEESS AKPGDIVVRD KAKGKKSKAA AKAGSSKYQW DIMKSLGLSD DDIVKFSEAE
     HWLDYFPPLA VQDLKTIGLK VDWRRSFITT DVNPYYDSFV RWQFLTLRER NKIKFGKRYT
     IYSPKDGQPC MDHDRQTGEG VGPQEYTLVK LKVLEPYPSK LSGLKGKNIF LVAATLRPET
     MFGQTNCWVR PDMKYIGFET ANGDIFICTQ RAARNMSYQG FTKHNGVVPV VKELMGEEIL
     GASLSAPLTC YKVVYVLPML TIKEDKGTGV VTSVPSDSPD DLAALRDLKK KQALRTKFGI
     RDDMVLPFEP VPVLEIPGIG NLPAVTVCDE LKIQSQNDRE KLAEAKEKLY LRGFYDGVML
     VDGFKGQKIQ HVKKTIQKNM IDAGDALIYM EPEKQVMSRS ADECVVALCD QWYLDYGDEN
     WKKQTFQCLK NMETFCEESR KNFEASLDWL QEHACSRTYG LGTRLPWDEQ WLIESLSDST
     IYMAFYTVAH LLQGGDLNGQ AESPLGIRPQ QMTKDVWDYV FFKDAPFPKT QIPKEKLDQL
     KQEFEFWYPV DLRASGKDLI PNHLSYYIYN HVAMWPEQSD KWPVSVRANG HLLLNSEKMS
     KSTGNFLTLS QAVDKFSADG MRLALADAGD TVEDANFVEA MADAGILRLY TWVEWVKEML
     ASCSSLRSGP ADSFNDRVFA SEMNAGIIKT DQNYEKMMFK EALKTGFFEF QAAKDKYREL
     ATEGMHRELV FRFIEVQTIL LTPFCPHLCE HIWTLLGKPD SIMHASWPVA GPVDESLIRS
     SQYLMEVAHD LRLRLKNYMM PAKGKKTDKQ PAQRPSHCTI YVAKNYPVWQ HITLTTLRSH
     FEANNGKLPD NKVIASELGS LPELKKYMKK VMPFVAMIKE NMEKKGPRVL DLELEFDEQA
     VLMENIVYLT NSLELEHIEV KFASEAEDKV REECCPGKPL NVFRTEPGVP VSLVNPQPSS
     GHFSTKIDIR QGDSCESIIR RLMKTDRGIK DLSKVKLMRF DDPLLGPRRV PVLGREHSEK
     TLISENAVFH VDLVSKKVHL TENGLRTDIG DTMVYLVH
//