ID SYWM_HUMAN Reviewed; 360 AA. AC Q9UGM6; B1ALR1; B2R9D4; Q53FT4; Q5VUD2; Q86TQ0; DT 06-JUN-2002, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=Tryptophan--tRNA ligase, mitochondrial; DE EC=6.1.1.2 {ECO:0000269|PubMed:10828066}; DE AltName: Full=(Mt)TrpRS; DE AltName: Full=Tryptophanyl-tRNA synthetase; DE Short=TrpRS; DE Flags: Precursor; GN Name=WARS2; 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), FUNCTION, CATALYTIC ACTIVITY, RP SUBCELLULAR LOCATION, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=10828066; DOI=10.1074/jbc.275.22.16820; RA Jorgensen R., Soegaard T.M.M., Rossing A.B., Martensen P.M., Justesen J.; RT "Identification and characterization of human mitochondrial tryptophanyl- RT tRNA synthetase."; RL J. Biol. Chem. 275:16820-16826(2000). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 MRNA] (ISOFORM 1). RC TISSUE=Kidney proximal tubule; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [5] 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP SER-50. RC TISSUE=Brain; 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 [7] 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 [8] 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 [9] {ECO:0007744|PDB:5EKD} RP X-RAY CRYSTALLOGRAPHY (1.82 ANGSTROMS) OF 18-360 IN COMPLEX WITH ATP; RP MANGANESE AND SUBSTRATE ANALOG. RA Williams T.L., Carter C.W.; RT "Binding of Mg2+ATP Enhances Inhibition of Human Mitochondrial RT Tryptophanyl-tRNA Synthetase by Indolmycin."; RL Submitted (NOV-2015) to the PDB data bank. RN [10] RP INVOLVEMENT IN NEMMLAS, AND VARIANTS NEMMLAS LEU-100 DEL AND MET-313. RX PubMed=28650581; DOI=10.1002/ajmg.a.38339; RA Theisen B.E., Rumyantseva A., Cohen J.S., Alcaraz W.A., Shinde D.N., RA Tang S., Srivastava S., Pevsner J., Trifunovic A., Fatemi A.; RT "Deficiency of WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, RT causes severe infantile onset leukoencephalopathy."; RL Am. J. Med. Genet. A 173:2505-2510(2017). RN [11] RP VARIANTS PKDYS3 GLY-13 AND TRP-228, AND INVOLVEMENT IN PKDYS3. RX PubMed=29120065; DOI=10.1111/cge.13172; RA Burke E.A., Frucht S.J., Thompson K., Wolfe L.A., Yokoyama T., Bertoni M., RA Huang Y., Sincan M., Adams D.R., Taylor R.W., Gahl W.A., Toro C., RA Malicdan M.C.V.; RT "Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause RT Levodopa-responsive infantile-onset Parkinsonism."; RL Clin. Genet. 93:712-718(2018). RN [12] RP INVOLVEMENT IN NEMMLAS, AND VARIANTS NEMMLAS VAL-45; GLN-77; LEU-178; RP MET-313; LEU-349 AND LYS-352. RX PubMed=28905505; DOI=10.1002/humu.23340; RA Wortmann S.B., Timal S., Venselaar H., Wintjes L.T., Kopajtich R., RA Feichtinger R.G., Onnekink C., Muehlmeister M., Brandt U., Smeitink J.A., RA Veltman J.A., Sperl W., Lefeber D., Pruijn G., Stojanovic V., RA Freisinger P., V Spronsen F., Derks T.G., Veenstra-Knol H.E., Mayr J.A., RA Roetig A., Tarnopolsky M., Prokisch H., Rodenburg R.J.; RT "Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA RT synthase in six individuals with mitochondrial encephalopathy."; RL Hum. Mutat. 38:1786-1795(2017). RN [13] RP VARIANT NEMMLAS GLY-13, CHARACTERIZATION OF VARIANT NEMMLAS GLY-13, RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INVOLVEMENT IN NEMMLAS. RX PubMed=28236339; DOI=10.1002/humu.23205; RA Musante L., Puettmann L., Kahrizi K., Garshasbi M., Hu H., Stehr H., RA Lipkowitz B., Otto S., Jensen L.R., Tzschach A., Jamali P., Wienker T., RA Najmabadi H., Ropers H.H., Kuss A.W.; RT "Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated RT in the aetiology of autosomal recessive intellectual disability."; RL Hum. Mutat. 38:621-636(2017). RN [14] RP VARIANTS NEMMLAS GLY-278 AND MET-313. RX PubMed=30920170; DOI=10.1002/mgg3.654; RA Maffezzini C., Laine I., Dallabona C., Clemente P., Calvo-Garrido J., RA Wibom R., Naess K., Barbaro M., Falk A., Donnini C., Freyer C., RA Wredenberg A., Wedell A.; RT "Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth RT retardation and progressive leukoencephalopathy."; RL Mol. Genet. Genomic Med. 7:e654-e654(2019). RN [15] RP VARIANTS PKDYS3 GLY-13 AND ASP-50, AND INVOLVEMENT IN PKDYS3. RX PubMed=31970218; DOI=10.1002/mdc3.12855; RA Huebers A., Huppertz H.J., Wortmann S.B., Kassubek J.; RT "Mutation of the WARS2 Gene as the Cause of a Severe Hyperkinetic Movement RT Disorder."; RL Mov. Disord. Clin. Pract. 7:88-90(2020). RN [16] RP VARIANTS PKDYS3 GLY-13; ASP-50; LEU-100 DEL AND 208-GLU--LEU-360 DEL. RX PubMed=34890876; DOI=10.1016/j.parkreldis.2021.11.030; RA Skorvanek M., Rektorova I., Mandemakers W., Wagner M., Steinfeld R., RA Orec L., Han V., Pavelekova P., Lackova A., Kulcsarova K., RA Ostrozovicova M., Gdovinova Z., Plecko B., Brunet T., Berutti R., RA Kuipers D.J.S., Boumeester V., Havrankova P., Tijssen M.A.J., RA Kaiyrzhanov R., Rizig M., Houlden H., Winkelmann J., Bonifati V., Zech M., RA Jech R.; RT "WARS2 mutations cause dopa-responsive early-onset parkinsonism and RT progressive myoclonus ataxia."; RL Parkinsonism Relat. Disord. 94:54-61(2022). RN [17] RP VARIANTS NEMMLAS GLY-278 AND MET-313. RX PubMed=35074316; DOI=10.1016/j.parkreldis.2022.01.012; RA Ilinca A., Kafantari E., Puschmann A.; RT "A relatively common hypomorphic variant in WARS2 causes monogenic RT disease."; RL Parkinsonism Relat. Disord. 94:129-131(2022). CC -!- FUNCTION: Catalyzes the attachment of tryptophan to tRNA(Trp) in a two- CC step reaction: tryptophan is first activated by ATP to form Trp-AMP and CC then transferred to the acceptor end of tRNA(Trp). CC {ECO:0000269|PubMed:10828066}. CC -!- CATALYTIC ACTIVITY: CC Reaction=tRNA(Trp) + L-tryptophan + ATP = L-tryptophyl-tRNA(Trp) + AMP CC + diphosphate + H(+); Xref=Rhea:RHEA:24080, Rhea:RHEA-COMP:9671, CC Rhea:RHEA-COMP:9705, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57912, ChEBI:CHEBI:78442, CC ChEBI:CHEBI:78535, ChEBI:CHEBI:456215; EC=6.1.1.2; CC Evidence={ECO:0000269|PubMed:10828066}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=27 uM for tryptophan {ECO:0000269|PubMed:10828066}; CC KM=401 uM for ATP {ECO:0000269|PubMed:10828066}; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix CC {ECO:0000269|PubMed:28236339}. Mitochondrion CC {ECO:0000269|PubMed:10828066}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9UGM6-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9UGM6-2; Sequence=VSP_041414, VSP_041415; CC -!- TISSUE SPECIFICITY: Brain. {ECO:0000269|PubMed:28236339}. CC -!- DISEASE: Neurodevelopmental disorder, mitochondrial, with abnormal CC movements and lactic acidosis, with or without seizures (NEMMLAS) CC [MIM:617710]: An autosomal recessive, mitochondrial disorder with a CC broad phenotypic spectrum ranging from severe neonatal lactic acidosis, CC encephalomyopathy and early death to an attenuated course with milder CC manifestations. Clinical features include delayed psychomotor CC development, intellectual disability, hypotonia, dystonia, ataxia, and CC spasticity. Severe combined respiratory chain deficiency may be found CC in severely affected individuals. {ECO:0000269|PubMed:28236339, CC ECO:0000269|PubMed:28650581, ECO:0000269|PubMed:28905505, CC ECO:0000269|PubMed:30920170, ECO:0000269|PubMed:35074316}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Parkinsonism-dystonia 3, childhood-onset (PKDYS3) CC [MIM:619738]: An autosomal recessive neurodegenerative disorder with CC onset in infancy or early childhood. Affected individuals present with CC progressive movement abnormalities, including parkinsonism with tremor, CC dystonia, myoclonus ataxia, and hyperkinetic movements such as CC ballismus. The parkinsonism features may be responsive to treatment CC with levodopa, although many patients develop levodopa-induced CC dyskinesia. Some patients may have mild cognitive impairment or CC psychiatric disturbances. {ECO:0000269|PubMed:29120065, CC ECO:0000269|PubMed:31970218, ECO:0000269|PubMed:34890876}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the class-I aminoacyl-tRNA synthetase family. CC {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; AJ242739; CAB63107.1; -; mRNA. DR EMBL; AK223197; BAD96917.1; -; mRNA. DR EMBL; AK313740; BAG36481.1; -; mRNA. DR EMBL; AL359823; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL139420; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL590288; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471122; EAW56693.1; -; Genomic_DNA. DR EMBL; BC044575; AAH44575.1; -; mRNA. DR EMBL; BC039889; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS30817.1; -. [Q9UGM6-2] DR CCDS; CCDS900.1; -. [Q9UGM6-1] DR RefSeq; NP_056651.1; NM_015836.4. [Q9UGM6-1] DR RefSeq; NP_957715.1; NM_201263.2. [Q9UGM6-2] DR PDB; 5EKD; X-ray; 1.82 A; A/B=18-360. DR PDBsum; 5EKD; -. DR AlphaFoldDB; Q9UGM6; -. DR SMR; Q9UGM6; -. DR BioGRID; 115633; 46. DR FunCoup; Q9UGM6; 1490. DR IntAct; Q9UGM6; 7. DR STRING; 9606.ENSP00000235521; -. DR DrugBank; DB00150; Tryptophan. DR GlyGen; Q9UGM6; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9UGM6; -. DR PhosphoSitePlus; Q9UGM6; -. DR BioMuta; WARS2; -. DR DMDM; 21362967; -. DR jPOST; Q9UGM6; -. DR MassIVE; Q9UGM6; -. DR PaxDb; 9606-ENSP00000235521; -. DR PeptideAtlas; Q9UGM6; -. DR ProteomicsDB; 84244; -. [Q9UGM6-1] DR ProteomicsDB; 84245; -. [Q9UGM6-2] DR Pumba; Q9UGM6; -. DR Antibodypedia; 33903; 78 antibodies from 27 providers. DR DNASU; 10352; -. DR Ensembl; ENST00000235521.5; ENSP00000235521.4; ENSG00000116874.13. [Q9UGM6-1] DR Ensembl; ENST00000369426.9; ENSP00000358434.5; ENSG00000116874.13. [Q9UGM6-2] DR GeneID; 10352; -. DR KEGG; hsa:10352; -. DR MANE-Select; ENST00000235521.5; ENSP00000235521.4; NM_015836.4; NP_056651.1. DR UCSC; uc001ehm.4; human. [Q9UGM6-1] DR AGR; HGNC:12730; -. DR ClinPGx; PA37341; -. DR CTD; 10352; -. DR DisGeNET; 10352; -. DR GeneCards; WARS2; -. DR GeneReviews; WARS2; -. DR HGNC; HGNC:12730; WARS2. DR HPA; ENSG00000116874; Low tissue specificity. DR MalaCards; WARS2; -. DR MIM; 604733; gene. DR MIM; 617710; phenotype. DR MIM; 619738; phenotype. DR OpenTargets; ENSG00000116874; -. DR Orphanet; 238455; Infantile dystonia-parkinsonism. DR Orphanet; 572798; WARS2-related combined oxidative phosphorylation defect. DR VEuPathDB; HostDB:ENSG00000116874; -. DR eggNOG; KOG2713; Eukaryota. DR GeneTree; ENSGT00940000153724; -. DR HOGENOM; CLU_029244_3_0_1; -. DR InParanoid; Q9UGM6; -. DR OMA; GWGQFKP; -. DR OrthoDB; 15808at2759; -. DR PAN-GO; Q9UGM6; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q9UGM6; -. DR BRENDA; 6.1.1.2; 2681. DR PathwayCommons; Q9UGM6; -. DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation. DR SignaLink; Q9UGM6; -. DR SIGNOR; Q9UGM6; -. DR Agora; ENSG00000116874; -. DR BioGRID-ORCS; 10352; 258 hits in 1189 CRISPR screens. DR ChiTaRS; WARS2; human. DR GeneWiki; WARS2; -. DR GenomeRNAi; 10352; -. DR Pharos; Q9UGM6; Tbio. DR PRO; PR:Q9UGM6; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q9UGM6; protein. DR Bgee; ENSG00000116874; Expressed in primordial germ cell in gonad and 144 other cell types or tissues. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004830; F:tryptophan-tRNA ligase activity; IDA:UniProtKB. DR GO; GO:0070183; P:mitochondrial tryptophanyl-tRNA aminoacylation; IBA:GO_Central. DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl. DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome. DR GO; GO:0001570; P:vasculogenesis; IEA:Ensembl. DR CDD; cd00806; TrpRS_core; 1. DR FunFam; 3.40.50.620:FF:000082; MSW1p Mitochondrial tryptophanyl-tRNA synthetase; 1. DR FunFam; 1.10.240.10:FF:000002; Tryptophan--tRNA ligase; 1. DR Gene3D; 3.40.50.620; HUPs; 1. DR Gene3D; 1.10.240.10; Tyrosyl-Transfer RNA Synthetase; 1. DR HAMAP; MF_00140_B; Trp_tRNA_synth_B; 1. DR InterPro; IPR001412; aa-tRNA-synth_I_CS. DR InterPro; IPR002305; aa-tRNA-synth_Ic. DR InterPro; IPR014729; Rossmann-like_a/b/a_fold. DR InterPro; IPR002306; Trp-tRNA-ligase. DR InterPro; IPR024109; Trp-tRNA-ligase_bac-type. DR InterPro; IPR050203; Trp-tRNA_synthetase. DR NCBIfam; TIGR00233; trpS; 1. DR PANTHER; PTHR43766; TRYPTOPHAN--TRNA LIGASE, MITOCHONDRIAL; 1. DR PANTHER; PTHR43766:SF1; TRYPTOPHAN--TRNA LIGASE, MITOCHONDRIAL; 1. DR Pfam; PF00579; tRNA-synt_1b; 1. DR PRINTS; PR01039; TRNASYNTHTRP. DR SUPFAM; SSF52374; Nucleotidylyl transferase; 1. DR PROSITE; PS00178; AA_TRNA_LIGASE_I; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Aminoacyl-tRNA synthetase; ATP-binding; KW Disease variant; Dystonia; Ligase; Mitochondrion; Nucleotide-binding; KW Parkinsonism; Primary mitochondrial disease; Protein biosynthesis; KW Proteomics identification; Reference proteome; Transit peptide. FT TRANSIT 1..18 FT /note="Mitochondrion" FT CHAIN 19..360 FT /note="Tryptophan--tRNA ligase, mitochondrial" FT /id="PRO_0000035828" FT BINDING 42 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 48..51 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 167 FT /ligand="L-tryptophan" FT /ligand_id="ChEBI:CHEBI:57912" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 179..181 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 217 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT BINDING 226..230 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0007744|PDB:5EKD" FT VAR_SEQ 212..220 FT /note="TSMKKVKSL -> SMCVLVFLT (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_041414" FT VAR_SEQ 221..360 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_041415" FT VARIANT 13 FT /note="W -> G (in NEMMLAS and PKDYS3; hypomorphic variant, FT clinically relevant when present in trans with an amorphic FT variant; impaired mitochondrial localization; FT dbSNP:rs139548132)" FT /evidence="ECO:0000269|PubMed:28236339, FT ECO:0000269|PubMed:29120065, ECO:0000269|PubMed:31970218, FT ECO:0000269|PubMed:34890876" FT /id="VAR_078435" FT VARIANT 45 FT /note="G -> V (in NEMMLAS; dbSNP:rs1553241795)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079734" FT VARIANT 50 FT /note="G -> D (in PKDYS3; dbSNP:rs1571323203)" FT /evidence="ECO:0000269|PubMed:31970218, FT ECO:0000269|PubMed:34890876" FT /id="VAR_086908" FT VARIANT 50 FT /note="G -> S (in dbSNP:rs11552864)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_028848" FT VARIANT 77 FT /note="H -> Q (in NEMMLAS; uncertain significance; FT dbSNP:rs766501807)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079735" FT VARIANT 100 FT /note="Missing (in NEMMLAS and PKDYS3; dbSNP:rs772867219)" FT /evidence="ECO:0000269|PubMed:28650581, FT ECO:0000269|PubMed:34890876" FT /id="VAR_079736" FT VARIANT 178 FT /note="V -> L (in NEMMLAS; dbSNP:rs912133959)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079737" FT VARIANT 208..360 FT /note="Missing (in PKDYS3)" FT /evidence="ECO:0000269|PubMed:34890876" FT /id="VAR_086909" FT VARIANT 228 FT /note="S -> W (in PKDYS3; dbSNP:rs1647600390)" FT /evidence="ECO:0000269|PubMed:29120065" FT /id="VAR_086910" FT VARIANT 267 FT /note="A -> P (in dbSNP:rs3790549)" FT /id="VAR_020217" FT VARIANT 278 FT /note="V -> G (in NEMMLAS; dbSNP:rs765904496)" FT /evidence="ECO:0000269|PubMed:30920170, FT ECO:0000269|PubMed:35074316" FT /id="VAR_086911" FT VARIANT 313 FT /note="K -> M (in NEMMLAS; dbSNP:rs145867327)" FT /evidence="ECO:0000269|PubMed:28650581, FT ECO:0000269|PubMed:28905505, ECO:0000269|PubMed:30920170, FT ECO:0000269|PubMed:35074316" FT /id="VAR_079738" FT VARIANT 349 FT /note="V -> L (in NEMMLAS; dbSNP:rs1170780314)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079739" FT VARIANT 352 FT /note="E -> K (in NEMMLAS; uncertain significance; FT dbSNP:rs563341344)" FT /evidence="ECO:0000269|PubMed:28905505" FT /id="VAR_079740" FT VARIANT 360 FT /note="L -> P (in dbSNP:rs17023101)" FT /id="VAR_052407" FT CONFLICT 151 FT /note="H -> R (in Ref. 3; BAD96917)" FT /evidence="ECO:0000305" FT STRAND 37..41 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 43..45 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 49..54 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 56..65 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 69..73 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 75..78 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 85..102 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 106..108 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 109..113 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 114..116 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 119..128 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 133..137 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 140..143 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 147..152 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 155..169 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 170..172 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 180..182 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 183..200 FT /evidence="ECO:0007829|PDB:5EKD" FT STRAND 208..210 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 213..216 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 234..236 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 244..253 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 266..268 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 270..283 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 287..293 FT /evidence="ECO:0007829|PDB:5EKD" FT TURN 294..296 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 299..324 FT /evidence="ECO:0007829|PDB:5EKD" FT HELIX 328..357 FT /evidence="ECO:0007829|PDB:5EKD" SQ SEQUENCE 360 AA; 40147 MW; 8C80DF6FCA214A91 CRC64; MALHSMRKAR ERWSFIRALH KGSAAAPALQ KDSKKRVFSG IQPTGILHLG NYLGAIESWV RLQDEYDSVL YSIVDLHSIT VPQDPAVLRQ SILDMTAVLL ACGINPEKSI LFQQSQVSEH TQLSWILSCM VRLPRLQHLH QWKAKTTKQK HDGTVGLLTY PVLQAADILL YKSTHVPVGE DQVQHMELVQ DLAQGFNKKY GEFFPVPESI LTSMKKVKSL RDPSAKMSKS DPDKLATVRI TDSPEEIVQK FRKAVTDFTS EVTYDPAGRA GVSNIVAVHA AVTGLSVEEV VRRSAGMNTA RYKLAVADAV IEKFAPIKRE IEKLKLDKDH LEKVLQIGSA KAKELAYTVC QEVKKLVGFL //