SYMM_HUMAN
ID SYMM_HUMAN Reviewed; 593 AA.
AC Q96GW9; A0AVC3; Q76E79; Q8IW62; Q8N7N4;
DT 10-JAN-2006, integrated into UniProtKB/Swiss-Prot.
DT 10-JAN-2006, sequence version 2.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Methionine--tRNA ligase, mitochondrial;
DE EC=6.1.1.10;
DE AltName: Full=Methionyl-tRNA synthetase 2;
DE AltName: Full=Mitochondrial methionyl-tRNA synthetase;
DE Short=MtMetRS;
DE Flags: Precursor;
GN Name=MARS2;
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].
RA Murata H., Takeuchi-Tomita N.;
RT "Downregulation of mitochondrial translation factors during the
RT differentiation of HL-60 cells by TPA.";
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Trachea;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Colon;
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 [5]
RP ENZYME ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=15274629; DOI=10.1021/bi049639w;
RA Spencer A.C., Heck A., Takeuchi N., Watanabe K., Spremulli L.L.;
RT "Characterization of the human mitochondrial methionyl-tRNA synthetase.";
RL Biochemistry 43:9743-9754(2004).
RN [6]
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 [7]
RP INVOLVEMENT IN SPAX3.
RX PubMed=22448145; DOI=10.1371/journal.pbio.1001288;
RA Bayat V., Thiffault I., Jaiswal M., Tetreault M., Donti T., Sasarman F.,
RA Bernard G., Demers-Lamarche J., Dicaire M.J., Mathieu J., Vanasse M.,
RA Bouchard J.P., Rioux M.F., Lourenco C.M., Li Z., Haueter C.,
RA Shoubridge E.A., Graham B.H., Brais B., Bellen H.J.;
RT "Mutations in the mitochondrial methionyl-tRNA synthetase cause a
RT neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in
RT humans.";
RL PLoS Biol. 10:E1001288-E1001288(2012).
RN [8]
RP INVOLVEMENT IN COXPD25, AND VARIANT COXPD25 TRP-142.
RX PubMed=25754315; DOI=10.1002/humu.22781;
RA Webb B.D., Wheeler P.G., Hagen J.J., Cohen N., Linderman M.D., Diaz G.A.,
RA Naidich T.P., Rodenburg R.J., Houten S.M., Schadt E.E.;
RT "Novel, compound heterozygous, single-nucleotide variants in MARS2
RT associated with developmental delay, poor growth, and sensorineural hearing
RT loss.";
RL Hum. Mutat. 36:587-592(2015).
RN [9]
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).
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-methionine + tRNA(Met) = AMP + diphosphate + L-
CC methionyl-tRNA(Met); Xref=Rhea:RHEA:13481, Rhea:RHEA-COMP:9667,
CC Rhea:RHEA-COMP:9698, ChEBI:CHEBI:30616, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57844, ChEBI:CHEBI:78442, ChEBI:CHEBI:78530,
CC ChEBI:CHEBI:456215; EC=6.1.1.10;
CC Evidence={ECO:0000269|PubMed:15274629};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=18 uM for Met {ECO:0000269|PubMed:15274629};
CC KM=85 uM for ATP {ECO:0000269|PubMed:15274629};
CC KM=2.1 uM for tRNA-Met {ECO:0000269|PubMed:15274629};
CC pH dependence:
CC Optimum pH is 7.8-8.2. {ECO:0000269|PubMed:15274629};
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000305}.
CC -!- DISEASE: Spastic ataxia 3, autosomal recessive (SPAX3) [MIM:611390]: A
CC neurologic disorder characterized by cerebellar ataxia, ataxic gait,
CC spasticity, and hyperreflexia. Other variable features include
CC dysarthria, dysmetria, mild cognitive impairment, urinary urgency and
CC dystonic positioning. {ECO:0000269|PubMed:22448145}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Combined oxidative phosphorylation deficiency 25 (COXPD25)
CC [MIM:616430]: A mitochondrial disorder resulting in developmental
CC delay, growth failure, and sensorineural hearing loss.
CC {ECO:0000269|PubMed:25754315}. 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=AAH09115.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH40934.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AB107013; BAC92749.1; -; mRNA.
DR EMBL; AK098121; BAC05238.1; -; mRNA.
DR EMBL; AC073058; AAX93244.1; -; Genomic_DNA.
DR EMBL; BC009115; AAH09115.1; ALT_INIT; mRNA.
DR EMBL; BC040934; AAH40934.1; ALT_INIT; mRNA.
DR EMBL; BC126294; AAI26295.1; -; mRNA.
DR CCDS; CCDS33358.1; -.
DR RefSeq; NP_612404.1; NM_138395.3.
DR AlphaFoldDB; Q96GW9; -.
DR SMR; Q96GW9; -.
DR BioGRID; 124988; 41.
DR IntAct; Q96GW9; 10.
DR STRING; 9606.ENSP00000282276; -.
DR BindingDB; Q96GW9; -.
DR ChEMBL; CHEMBL4739700; -.
DR DrugBank; DB00134; Methionine.
DR GlyGen; Q96GW9; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96GW9; -.
DR PhosphoSitePlus; Q96GW9; -.
DR BioMuta; MARS2; -.
DR DMDM; 85541638; -.
DR EPD; Q96GW9; -.
DR jPOST; Q96GW9; -.
DR MassIVE; Q96GW9; -.
DR MaxQB; Q96GW9; -.
DR PaxDb; Q96GW9; -.
DR PeptideAtlas; Q96GW9; -.
DR PRIDE; Q96GW9; -.
DR ProteomicsDB; 76673; -.
DR Antibodypedia; 50280; 123 antibodies from 23 providers.
DR DNASU; 92935; -.
DR Ensembl; ENST00000282276.8; ENSP00000282276.6; ENSG00000247626.5.
DR GeneID; 92935; -.
DR KEGG; hsa:92935; -.
DR MANE-Select; ENST00000282276.8; ENSP00000282276.6; NM_138395.4; NP_612404.1.
DR UCSC; uc002uuq.4; human.
DR CTD; 92935; -.
DR DisGeNET; 92935; -.
DR GeneCards; MARS2; -.
DR HGNC; HGNC:25133; MARS2.
DR HPA; ENSG00000247626; Low tissue specificity.
DR MalaCards; MARS2; -.
DR MIM; 609728; gene.
DR MIM; 611390; phenotype.
DR MIM; 616430; phenotype.
DR neXtProt; NX_Q96GW9; -.
DR OpenTargets; ENSG00000247626; -.
DR Orphanet; 314603; Autosomal recessive spastic ataxia with leukoencephalopathy.
DR Orphanet; 447954; Combined oxidative phosphorylation defect type 25.
DR PharmGKB; PA134863396; -.
DR VEuPathDB; HostDB:ENSG00000247626; -.
DR eggNOG; KOG0436; Eukaryota.
DR GeneTree; ENSGT00550000075136; -.
DR HOGENOM; CLU_009710_9_0_1; -.
DR InParanoid; Q96GW9; -.
DR OMA; SDMHGTP; -.
DR OrthoDB; 788159at2759; -.
DR PhylomeDB; Q96GW9; -.
DR TreeFam; TF105709; -.
DR PathwayCommons; Q96GW9; -.
DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation.
DR SignaLink; Q96GW9; -.
DR BioGRID-ORCS; 92935; 613 hits in 1084 CRISPR screens.
DR GenomeRNAi; 92935; -.
DR Pharos; Q96GW9; Tbio.
DR PRO; PR:Q96GW9; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q96GW9; protein.
DR Bgee; ENSG00000247626; Expressed in tibialis anterior and 110 other tissues.
DR Genevisible; Q96GW9; HS.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004825; F:methionine-tRNA ligase activity; IDA:UniProtKB.
DR GO; GO:0006431; P:methionyl-tRNA aminoacylation; IDA:UniProtKB.
DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome.
DR CDD; cd07957; Anticodon_Ia_Met; 1.
DR CDD; cd00814; MetRS_core; 1.
DR Gene3D; 3.40.50.620; -; 1.
DR InterPro; IPR041872; Anticodon_Met.
DR InterPro; IPR014758; Met-tRNA_synth.
DR InterPro; IPR023457; Met-tRNA_synth_2.
DR InterPro; IPR015413; Methionyl/Leucyl_tRNA_Synth.
DR InterPro; IPR033911; MetRS_core.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR InterPro; IPR009080; tRNAsynth_Ia_anticodon-bd.
DR PANTHER; PTHR43326; PTHR43326; 1.
DR Pfam; PF19303; Anticodon_3; 1.
DR Pfam; PF09334; tRNA-synt_1g; 1.
DR PRINTS; PR01041; TRNASYNTHMET.
DR SUPFAM; SSF47323; SSF47323; 1.
DR TIGRFAMs; TIGR00398; metG; 1.
PE 1: Evidence at protein level;
KW Aminoacyl-tRNA synthetase; ATP-binding; Deafness; Disease variant; Ligase;
KW Mitochondrion; Neurodegeneration; Nucleotide-binding;
KW Primary mitochondrial disease; Protein biosynthesis; Reference proteome;
KW Transit peptide.
FT TRANSIT 1..29
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 30..593
FT /note="Methionine--tRNA ligase, mitochondrial"
FT /id="PRO_0000045493"
FT MOTIF 52..62
FT /note="'HIGH' region"
FT MOTIF 347..351
FT /note="'KMSKS' region"
FT BINDING 350
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT VARIANT 142
FT /note="R -> W (in COXPD25; dbSNP:rs794726870)"
FT /evidence="ECO:0000269|PubMed:25754315"
FT /id="VAR_073858"
FT CONFLICT 535..536
FT /note="LL -> MM (in Ref. 1; BAC92749)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 593 AA; 66591 MW; A5076FD9F31F4B96 CRC64;
MLRTSVLRLL GRTGASRLSL LEDFGPRYYS SGSLSAGDDA CDVRAYFTTP IFYVNAAPHI
GHLYSALLAD ALCRHRRLRG PSTAATRFST GTDEHGLKIQ QAAATAGLAP TELCDRVSEQ
FQQLFQEAGI SCTDFIRTTE ARHRVAVQHF WGVLKSRGLL YKGVYEGWYC ASDECFLPEA
KVTQQPGPSG DSFPVSLESG HPVSWTKEEN YIFRLSQFRK PLQRWLRGNP QAITPEPFHH
VVLQWLDEEL PDLSVSRRSS HLHWGIPVPG DDSQTIYVWL DALVNYLTVI GYPNAEFKSW
WPATSHIIGK DILKFHAIYW PAFLLGAGMS PPQRICVHSH WTVCGQKMSK SLGNVVDPRT
CLNRYTVDGF RYFLLRQGVP NWDCDYYDEK VVKLLNSELA DALGGLLNRC TAKRINPSET
YPAFCTTCFP SEPGLVGPSV RAQAEDYALV SAVATLPKQV ADHYDNFRIY KALEAVSSCV
RQTNGFVQRH APWKLNWESP VDAPWLGTVL HVALECLRVF GTLLQPVTPS LADKLLSRLG
VSASERSLGE LYFLPRFYGH PCPFEGRRLG PETGLLFPRL DQSRTWLVKA HRT
