HARS1_HUMAN
ID HARS1_HUMAN Reviewed; 509 AA.
AC P12081; B4DHQ1; B4DY73; D6REN6; J3KNE5;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1992, sequence version 2.
DT 03-AUG-2022, entry version 222.
DE RecName: Full=Histidine--tRNA ligase, cytoplasmic;
DE EC=6.1.1.21 {ECO:0000269|PubMed:29235198};
DE AltName: Full=Histidyl-tRNA synthetase;
DE Short=HisRS;
GN Name=HARS1 {ECO:0000312|HGNC:HGNC:4816}; Synonyms=HARS, HRS;
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).
RX PubMed=1549469; DOI=10.1093/nar/20.5.1075;
RA Raben N., Borriello F., Amin J., Horwitz R., Fraser D., Plotz P.;
RT "Human histidyl-tRNA synthetase: recognition of amino acid signature
RT regions in class 2a aminoacyl-tRNA synthetases.";
RL Nucleic Acids Res. 20:1075-1081(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3554142; DOI=10.1093/nar/15.8.3349;
RA Tsui F.W.L., Siminovitch L.;
RT "Isolation, structure and expression of mammalian genes for histidyl-tRNA
RT synthetase.";
RL Nucleic Acids Res. 15:3349-3367(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Caudate nucleus, and Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Brain;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RT "Homo sapiens protein coding cDNA.";
RL Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, and Uterus;
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 NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-30.
RX PubMed=8406012; DOI=10.1016/0378-1119(93)90294-d;
RA Tsui H.W., Mok S., de Souza L., Martin A., Tsui F.W.L.;
RT "Transcriptional analyses of the gene region that encodes human histidyl-
RT tRNA synthetase: identification of a novel bidirectional regulatory
RT element.";
RL Gene 131:201-208(1993).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-30.
RX PubMed=7755634; DOI=10.1006/bbrc.1995.1696;
RA O'Hanlon T.P., Raben N., Miller F.W.;
RT "A novel gene oriented in a head-to-head configuration with the human
RT histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a
RT polypeptide homologous to HRS.";
RL Biochem. Biophys. Res. Commun. 210:556-566(1995).
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
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 [11]
RP INVOLVEMENT IN CMT2W, VARIANTS GLU-5; ASP-205 AND ARG-376, VARIANTS CMT2W
RP GLN-137; ALA-238 AND SER-505, AND CHARACTERIZATION OF VARIANT CMT2W
RP GLN-137.
RX PubMed=22930593; DOI=10.1002/humu.22210;
RG NISC comparative sequencing program;
RA Vester A., Velez-Ruiz G., McLaughlin H.M., Lupski J.R., Talbot K.,
RA Vance J.M., Zuchner S., Roda R.H., Fischbeck K.H., Biesecker L.G.,
RA Nicholson G., Beg A.A., Antonellis A.;
RT "A loss-of-function variant in the human histidyl-tRNA synthetase (HARS)
RT gene is neurotoxic in vivo.";
RL Hum. Mutat. 34:191-199(2013).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [13]
RP FUNCTION, INVOLVEMENT IN CMT2W, VARIANTS CMT2W ILE-132; HIS-134; GLU-175
RP AND TYR-364, AND CHARACTERIZATION OF VARIANTS CMT2W ILE-132; HIS-134;
RP GLU-175 AND TYR-364.
RX PubMed=26072516; DOI=10.1093/brain/awv158;
RA Safka Brozkova D., Deconinck T., Griffin L.B., Ferbert A., Haberlova J.,
RA Mazanec R., Lassuthova P., Roth C., Pilunthanakul T., Rautenstrauss B.,
RA Janecke A.R., Zavadakova P., Chrast R., Rivolta C., Zuchner S.,
RA Antonellis A., Beg A.A., De Jonghe P., Senderek J., Seeman P., Baets J.;
RT "Loss of function mutations in HARS cause a spectrum of inherited
RT peripheral neuropathies.";
RL Brain 138:2161-2172(2015).
RN [14]
RP STRUCTURE BY NMR OF 1-60.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structures of the WHEP-TRS domain of human histidyl-tRNA
RT synthetase.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [15] {ECO:0007744|PDB:4PHC}
RP X-RAY CRYSTALLOGRAPHY (2.84 ANGSTROMS) IN COMPLEX WITH L-HISTIDINE, AND
RP SUBUNIT.
RX PubMed=25151410; DOI=10.1016/j.biochi.2014.08.005;
RA Koh C.Y., Wetzel A.B., de van der Schueren W.J., Hol W.G.;
RT "Comparison of histidine recognition in human and trypanosomatid histidyl-
RT tRNA synthetases.";
RL Biochimie 106:111-120(2014).
RN [16] {ECO:0007744|PDB:4X5O}
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS), AND SUBUNIT.
RA Kim Y.K., Chang J.E., Kim S., Jeon Y.H.;
RT "Structural characteristics of human histidyl-tRNA synthetase.";
RL Biodesign 2:142-148(2015).
RN [17]
RP VARIANT USH3B SER-454.
RX PubMed=22279524; DOI=10.1371/journal.pone.0028936;
RA Puffenberger E.G., Jinks R.N., Sougnez C., Cibulskis K., Willert R.A.,
RA Achilly N.P., Cassidy R.P., Fiorentini C.J., Heiken K.F., Lawrence J.J.,
RA Mahoney M.H., Miller C.J., Nair D.T., Politi K.A., Worcester K.N.,
RA Setton R.A., Dipiazza R., Sherman E.A., Eastman J.T., Francklyn C.,
RA Robey-Bond S., Rider N.L., Gabriel S., Morton D.H., Strauss K.A.;
RT "Genetic mapping and exome sequencing identify variants associated with
RT five novel diseases.";
RL PLoS ONE 7:E28936-E28936(2012).
RN [18]
RP VARIANTS CMT2W GLY-155; CYS-330 AND ASN-356, CHARACTERIZATION OF VARIANTS
RP CMT2W GLY-155; CYS-330 AND ASN-356, CATALYTIC ACTIVITY, FUNCTION,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT.
RX PubMed=29235198; DOI=10.1002/humu.23380;
RA Abbott J.A., Meyer-Schuman R., Lupo V., Feely S., Mademan I., Oprescu S.N.,
RA Griffin L.B., Alberti M.A., Casasnovas C., Aharoni S., Basel-Vanagaite L.,
RA Zuechner S., De Jonghe P., Baets J., Shy M.E., Espinos C., Demeler B.,
RA Antonellis A., Francklyn C.;
RT "Substrate interaction defects in histidyl-tRNA synthetase linked to
RT dominant axonal peripheral neuropathy.";
RL Hum. Mutat. 39:415-432(2018).
CC -!- FUNCTION: Catalyzes the ATP-dependent ligation of histidine to the 3'-
CC end of its cognate tRNA, via the formation of an aminoacyl-adenylate
CC intermediate (His-AMP) (PubMed:29235198). Plays a role in axon guidance
CC (PubMed:26072516). {ECO:0000269|PubMed:26072516,
CC ECO:0000269|PubMed:29235198}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-histidine + tRNA(His) = AMP + diphosphate + H(+) + L-
CC histidyl-tRNA(His); Xref=Rhea:RHEA:17313, Rhea:RHEA-COMP:9665,
CC Rhea:RHEA-COMP:9689, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57595, ChEBI:CHEBI:78442,
CC ChEBI:CHEBI:78527, ChEBI:CHEBI:456215; EC=6.1.1.21;
CC Evidence={ECO:0000269|PubMed:29235198};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=8.0 uM for histidine {ECO:0000269|PubMed:29235198};
CC KM=0.872 uM for tRNA(His) {ECO:0000269|PubMed:29235198};
CC KM=44.2 uM for ATP {ECO:0000269|PubMed:29235198};
CC Note=kcat is 5.4 sec(-1) for aminoacylation of tRNA(His)
CC (PubMed:29235198). kcat is 4.1 sec(-1) for histidine.
CC (PubMed:29235198). kcat is 5.8 sec(-1) for ATP (PubMed:29235198).
CC {ECO:0000269|PubMed:29235198};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:25151410,
CC ECO:0000269|PubMed:29235198, ECO:0000269|Ref.16}.
CC -!- INTERACTION:
CC P12081; P12081: HARS1; NbExp=2; IntAct=EBI-1057566, EBI-1057566;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:F1Q5D5}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P12081-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P12081-2; Sequence=VSP_045118;
CC Name=3;
CC IsoId=P12081-3; Sequence=VSP_045118, VSP_046662;
CC Name=4;
CC IsoId=P12081-4; Sequence=VSP_046662;
CC -!- TISSUE SPECIFICITY: Brain, heart, liver and kidney.
CC -!- DISEASE: Usher syndrome 3B (USH3B) [MIM:614504]: A syndrome
CC characterized by progressive vision and hearing loss during early
CC childhood. Some patients have the so-called 'Charles Bonnet syndrome,'
CC involving decreased visual acuity and vivid visual hallucinations. USH
CC is a genetically heterogeneous condition characterized by the
CC association of retinitis pigmentosa with sensorineural deafness. Age at
CC onset and differences in auditory and vestibular function distinguish
CC Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher
CC syndrome type 3 (USH3). USH3 is characterized by postlingual,
CC progressive hearing loss, variable vestibular dysfunction, and onset of
CC retinitis pigmentosa symptoms, including nyctalopia, constriction of
CC the visual fields, and loss of central visual acuity, usually by the
CC second decade of life. {ECO:0000269|PubMed:22279524}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2W (CMT2W) [MIM:616625]: An
CC autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later of
CC the distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited) and
CC primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2
CC group are characterized by signs of axonal degeneration in the absence
CC of obvious myelin alterations, normal or slightly reduced nerve
CC conduction velocities, and progressive distal muscle weakness and
CC atrophy. CMT2W patients manifest a peripheral neuropathy mainly
CC affecting the lower limbs and resulting in gait difficulties and distal
CC sensory impairment. Most patients also have upper limb involvement.
CC {ECO:0000269|PubMed:22930593, ECO:0000269|PubMed:26072516,
CC ECO:0000269|PubMed:29235198}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA28956.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; Z11518; CAA77607.1; -; mRNA.
DR EMBL; X05345; CAA28956.1; ALT_FRAME; mRNA.
DR EMBL; AK295219; BAG58213.1; -; mRNA.
DR EMBL; AK302295; BAG63635.1; -; mRNA.
DR EMBL; AK225776; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC116353; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC011807; AAH11807.1; -; mRNA.
DR EMBL; BC080514; AAH80514.1; -; mRNA.
DR EMBL; M96646; AAA58668.1; -; Genomic_DNA.
DR EMBL; U18936; AAA73973.1; -; Genomic_DNA.
DR CCDS; CCDS4237.1; -. [P12081-1]
DR CCDS; CCDS58976.1; -. [P12081-2]
DR CCDS; CCDS58977.1; -. [P12081-3]
DR CCDS; CCDS58978.1; -. [P12081-4]
DR PIR; I37559; SYHUHT.
DR RefSeq; NP_001244969.1; NM_001258040.2. [P12081-2]
DR RefSeq; NP_001244970.1; NM_001258041.2. [P12081-4]
DR RefSeq; NP_001244971.1; NM_001258042.2. [P12081-3]
DR RefSeq; NP_002100.2; NM_002109.5. [P12081-1]
DR PDB; 1X59; NMR; -; A=1-60.
DR PDB; 2LW7; NMR; -; A=2-60, A=399-509.
DR PDB; 4G84; X-ray; 2.40 A; A/B=54-506.
DR PDB; 4G85; X-ray; 3.11 A; A/B=1-506.
DR PDB; 4PHC; X-ray; 2.84 A; A/B/C/D=1-509.
DR PDB; 4X5O; X-ray; 2.80 A; A/B=1-509.
DR PDB; 5W6M; X-ray; 3.70 A; A/B=54-503.
DR PDB; 6O76; X-ray; 2.79 A; A/B=1-509.
DR PDBsum; 1X59; -.
DR PDBsum; 2LW7; -.
DR PDBsum; 4G84; -.
DR PDBsum; 4G85; -.
DR PDBsum; 4PHC; -.
DR PDBsum; 4X5O; -.
DR PDBsum; 5W6M; -.
DR PDBsum; 6O76; -.
DR AlphaFoldDB; P12081; -.
DR SMR; P12081; -.
DR BioGRID; 109285; 64.
DR DIP; DIP-37596N; -.
DR IntAct; P12081; 14.
DR MINT; P12081; -.
DR STRING; 9606.ENSP00000425634; -.
DR BindingDB; P12081; -.
DR ChEMBL; CHEMBL4002; -.
DR DrugBank; DB00117; Histidine.
DR GlyGen; P12081; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P12081; -.
DR MetOSite; P12081; -.
DR PhosphoSitePlus; P12081; -.
DR SwissPalm; P12081; -.
DR BioMuta; HARS; -.
DR DMDM; 135123; -.
DR EPD; P12081; -.
DR jPOST; P12081; -.
DR MassIVE; P12081; -.
DR MaxQB; P12081; -.
DR PaxDb; P12081; -.
DR PeptideAtlas; P12081; -.
DR PRIDE; P12081; -.
DR ProteomicsDB; 14349; -.
DR ProteomicsDB; 52824; -. [P12081-1]
DR ProteomicsDB; 5502; -.
DR ABCD; P12081; 2 sequenced antibodies.
DR Antibodypedia; 15372; 292 antibodies from 32 providers.
DR DNASU; 3035; -.
DR Ensembl; ENST00000307633.7; ENSP00000304668.3; ENSG00000170445.16. [P12081-3]
DR Ensembl; ENST00000438307.6; ENSP00000411511.2; ENSG00000170445.16. [P12081-2]
DR Ensembl; ENST00000457527.6; ENSP00000387893.2; ENSG00000170445.16. [P12081-4]
DR Ensembl; ENST00000504156.7; ENSP00000425634.1; ENSG00000170445.16. [P12081-1]
DR GeneID; 3035; -.
DR KEGG; hsa:3035; -.
DR MANE-Select; ENST00000504156.7; ENSP00000425634.1; NM_002109.6; NP_002100.2.
DR UCSC; uc003lgv.6; human. [P12081-1]
DR CTD; 3035; -.
DR DisGeNET; 3035; -.
DR GeneCards; HARS1; -.
DR GeneReviews; HARS1; -.
DR HGNC; HGNC:4816; HARS1.
DR HPA; ENSG00000170445; Low tissue specificity.
DR MalaCards; HARS1; -.
DR MIM; 142810; gene.
DR MIM; 614504; phenotype.
DR MIM; 616625; phenotype.
DR neXtProt; NX_P12081; -.
DR OpenTargets; ENSG00000170445; -.
DR Orphanet; 488333; Autosomal dominant Charcot-Marie-Tooth disease type 2W.
DR Orphanet; 231183; Usher syndrome type 3.
DR PharmGKB; PA29191; -.
DR VEuPathDB; HostDB:ENSG00000170445; -.
DR eggNOG; KOG1936; Eukaryota.
DR GeneTree; ENSGT00390000005922; -.
DR InParanoid; P12081; -.
DR OMA; CDFDFIG; -.
DR OrthoDB; 1065556at2759; -.
DR PhylomeDB; P12081; -.
DR TreeFam; TF300652; -.
DR BRENDA; 6.1.1.21; 2681.
DR PathwayCommons; P12081; -.
DR Reactome; R-HSA-379716; Cytosolic tRNA aminoacylation.
DR SignaLink; P12081; -.
DR BioGRID-ORCS; 3035; 734 hits in 1079 CRISPR screens.
DR ChiTaRS; HARS; human.
DR EvolutionaryTrace; P12081; -.
DR GeneWiki; HARS; -.
DR GenomeRNAi; 3035; -.
DR Pharos; P12081; Tchem.
DR PRO; PR:P12081; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P12081; protein.
DR Bgee; ENSG00000170445; Expressed in lateral nuclear group of thalamus and 196 other tissues.
DR ExpressionAtlas; P12081; baseline and differential.
DR Genevisible; P12081; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:WormBase.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004821; F:histidine-tRNA ligase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0006427; P:histidyl-tRNA aminoacylation; IDA:UniProtKB.
DR GO; GO:0032543; P:mitochondrial translation; IBA:GO_Central.
DR GO; GO:0006412; P:translation; NAS:UniProtKB.
DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome.
DR CDD; cd00773; HisRS-like_core; 1.
DR CDD; cd00859; HisRS_anticodon; 1.
DR DisProt; DP01668; -.
DR Gene3D; 3.30.930.10; -; 1.
DR Gene3D; 3.40.50.800; -; 1.
DR HAMAP; MF_00127; His_tRNA_synth; 1.
DR InterPro; IPR006195; aa-tRNA-synth_II.
DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL.
DR InterPro; IPR004154; Anticodon-bd.
DR InterPro; IPR036621; Anticodon-bd_dom_sf.
DR InterPro; IPR015807; His-tRNA-ligase.
DR InterPro; IPR041715; HisRS-like_core.
DR InterPro; IPR004516; HisRS/HisZ.
DR InterPro; IPR033656; HisRS_anticodon.
DR InterPro; IPR009068; S15_NS1_RNA-bd.
DR InterPro; IPR000738; WHEP-TRS_dom.
DR Pfam; PF03129; HGTP_anticodon; 1.
DR Pfam; PF13393; tRNA-synt_His; 1.
DR Pfam; PF00458; WHEP-TRS; 1.
DR PIRSF; PIRSF001549; His-tRNA_synth; 1.
DR SMART; SM00991; WHEP-TRS; 1.
DR SUPFAM; SSF47060; SSF47060; 1.
DR SUPFAM; SSF55681; SSF55681; 1.
DR TIGRFAMs; TIGR00442; hisS; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
DR PROSITE; PS00762; WHEP_TRS_1; 1.
DR PROSITE; PS51185; WHEP_TRS_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Aminoacyl-tRNA synthetase;
KW ATP-binding; Charcot-Marie-Tooth disease; Cytoplasm; Deafness;
KW Disease variant; Ligase; Neurodegeneration; Neuropathy; Nucleotide-binding;
KW Phosphoprotein; Protein biosynthesis; Reference proteome;
KW Retinitis pigmentosa; Usher syndrome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:19413330"
FT CHAIN 2..509
FT /note="Histidine--tRNA ligase, cytoplasmic"
FT /id="PRO_0000136332"
FT DOMAIN 3..59
FT /note="WHEP-TRS"
FT BINDING 130..132
FT /ligand="L-histidine"
FT /ligand_id="ChEBI:CHEBI:57595"
FT /evidence="ECO:0000269|PubMed:25151410,
FT ECO:0007744|PDB:4PHC"
FT BINDING 157
FT /ligand="L-histidine"
FT /ligand_id="ChEBI:CHEBI:57595"
FT /evidence="ECO:0000269|PubMed:25151410,
FT ECO:0007744|PDB:4PHC"
FT BINDING 173
FT /ligand="L-histidine"
FT /ligand_id="ChEBI:CHEBI:57595"
FT /evidence="ECO:0000269|PubMed:25151410,
FT ECO:0007744|PDB:4PHC"
FT BINDING 177
FT /ligand="L-histidine"
FT /ligand_id="ChEBI:CHEBI:57595"
FT /evidence="ECO:0000269|PubMed:25151410,
FT ECO:0007744|PDB:4PHC"
FT BINDING 326
FT /ligand="L-histidine"
FT /ligand_id="ChEBI:CHEBI:57595"
FT /evidence="ECO:0000269|PubMed:25151410,
FT ECO:0007744|PDB:4PHC"
FT BINDING 330..331
FT /ligand="L-histidine"
FT /ligand_id="ChEBI:CHEBI:57595"
FT /evidence="ECO:0000269|PubMed:25151410,
FT ECO:0007744|PDB:4PHC"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:19413330"
FT MOD_RES 66
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99KK9"
FT MOD_RES 356
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VAR_SEQ 60..99
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045118"
FT VAR_SEQ 155..174
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039, ECO:0000303|Ref.4"
FT /id="VSP_046662"
FT VARIANT 5
FT /note="A -> E (in dbSNP:rs78741041)"
FT /evidence="ECO:0000269|PubMed:22930593"
FT /id="VAR_069021"
FT VARIANT 132
FT /note="T -> I (in CMT2W; loss-of-function variant;
FT dbSNP:rs143473232)"
FT /evidence="ECO:0000269|PubMed:26072516"
FT /id="VAR_075064"
FT VARIANT 134
FT /note="P -> H (in CMT2W; loss-of-function variant;
FT dbSNP:rs863225122)"
FT /evidence="ECO:0000269|PubMed:26072516"
FT /id="VAR_075065"
FT VARIANT 137
FT /note="R -> Q (in CMT2W; has a neurotoxic effect in an
FT animal model; results in loss of function;
FT dbSNP:rs191391414)"
FT /evidence="ECO:0000269|PubMed:22930593"
FT /id="VAR_069022"
FT VARIANT 155
FT /note="V -> G (in CMT2W; unknown pathological significance;
FT fails to complement deletion of the yeast ortholog;
FT decreases histidine-tRNA ligase activity; increases in the
FT KM for ATP binding; does not disrupt dimerization;
FT dbSNP:rs1239341211)"
FT /evidence="ECO:0000269|PubMed:29235198"
FT /id="VAR_083003"
FT VARIANT 175
FT /note="D -> E (in CMT2W; hypomorphic variant;
FT dbSNP:rs863225123)"
FT /evidence="ECO:0000269|PubMed:26072516"
FT /id="VAR_075066"
FT VARIANT 205
FT /note="G -> D (in dbSNP:rs147288996)"
FT /evidence="ECO:0000269|PubMed:22930593"
FT /id="VAR_069023"
FT VARIANT 238
FT /note="V -> A (in CMT2W; unknown pathological significance;
FT dbSNP:rs536175170)"
FT /evidence="ECO:0000269|PubMed:22930593"
FT /id="VAR_069024"
FT VARIANT 330
FT /note="Y -> C (in CMT2W; fails to complement deletion of
FT the yeast ortholog; decreases histidine-tRNA ligase
FT activity; increases in the KM for ATP binding; does not
FT disrupt dimerization; dbSNP:rs1554106881)"
FT /evidence="ECO:0000269|PubMed:29235198"
FT /id="VAR_083004"
FT VARIANT 356
FT /note="S -> N (in CMT2W; unknown pathological significance;
FT fails to complement deletion of the yeast ortholog;
FT decreases histidine-tRNA ligase activity; increases in the
FT KM for ATP binding; does not disrupt dimerization;
FT dbSNP:rs144322728)"
FT /evidence="ECO:0000269|PubMed:29235198"
FT /id="VAR_083005"
FT VARIANT 364
FT /note="D -> Y (in CMT2W; loss-of-function variant;
FT dbSNP:rs863225124)"
FT /evidence="ECO:0000269|PubMed:26072516"
FT /id="VAR_075067"
FT VARIANT 376
FT /note="K -> R (in dbSNP:rs139447495)"
FT /evidence="ECO:0000269|PubMed:22930593"
FT /id="VAR_069025"
FT VARIANT 399
FT /note="A -> V (in dbSNP:rs34732372)"
FT /id="VAR_061908"
FT VARIANT 454
FT /note="Y -> S (in USH3B; dbSNP:rs387906639)"
FT /evidence="ECO:0000269|PubMed:22279524"
FT /id="VAR_067918"
FT VARIANT 505
FT /note="P -> S (in CMT2W; unknown pathological significance;
FT dbSNP:rs747156884)"
FT /evidence="ECO:0000269|PubMed:22930593"
FT /id="VAR_069026"
FT CONFLICT 6
FT /note="A -> P (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 126
FT /note="S -> P (in Ref. 3; BAG58213)"
FT /evidence="ECO:0000305"
FT CONFLICT 165
FT /note="R -> G (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 181
FT /note="N -> Q (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 186
FT /note="I -> N (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 191
FT /note="C -> S (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 206
FT /note="D -> N (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 223
FT /note="I -> V (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 227
FT /note="S -> P (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 284
FT /note="L -> V (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 347
FT /note="A -> E (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 373..374
FT /note="KG -> QR (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT CONFLICT 375
FT /note="R -> L (in Ref. 3; BAG58213)"
FT /evidence="ECO:0000305"
FT CONFLICT 493
FT /note="D -> E (in Ref. 2; CAA28956)"
FT /evidence="ECO:0000305"
FT HELIX 3..23
FT /evidence="ECO:0007829|PDB:6O76"
FT HELIX 28..44
FT /evidence="ECO:0007829|PDB:6O76"
FT HELIX 67..86
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 96..99
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 100..103
FT /evidence="ECO:0007829|PDB:4G84"
FT TURN 104..106
FT /evidence="ECO:0007829|PDB:4PHC"
FT HELIX 109..113
FT /evidence="ECO:0007829|PDB:4PHC"
FT STRAND 120..122
FT /evidence="ECO:0007829|PDB:4X5O"
FT STRAND 125..127
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 132..141
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 147..156
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 163..166
FT /evidence="ECO:0007829|PDB:6O76"
FT STRAND 169..180
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 186..202
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 207..213
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 214..224
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 228..238
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 239..242
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 246..255
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 261..271
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 274..276
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 277..283
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 287..290
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 293..311
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 315..317
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 318..321
FT /evidence="ECO:0007829|PDB:4G84"
FT TURN 328..330
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 332..342
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 352..362
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 367..369
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 371..373
FT /evidence="ECO:0007829|PDB:4G85"
FT STRAND 379..384
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 386..398
FT /evidence="ECO:0007829|PDB:4G84"
FT TURN 399..401
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 411..414
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 416..419
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 421..433
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 438..440
FT /evidence="ECO:0007829|PDB:6O76"
FT STRAND 442..445
FT /evidence="ECO:0007829|PDB:4X5O"
FT HELIX 448..458
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 462..465
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 468..473
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 475..480
FT /evidence="ECO:0007829|PDB:4G84"
FT TURN 481..483
FT /evidence="ECO:0007829|PDB:4G84"
FT STRAND 486..490
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 491..493
FT /evidence="ECO:0007829|PDB:4G84"
FT HELIX 494..502
FT /evidence="ECO:0007829|PDB:4G84"
SQ SEQUENCE 509 AA; 57411 MW; 65D8BB71CE79B1FF CRC64;
MAERAALEEL VKLQGERVRG LKQQKASAEL IEEEVAKLLK LKAQLGPDES KQKFVLKTPK
GTRDYSPRQM AVREKVFDVI IRCFKRHGAE VIDTPVFELK ETLMGKYGED SKLIYDLKDQ
GGELLSLRYD LTVPFARYLA MNKLTNIKRY HIAKVYRRDN PAMTRGRYRE FYQCDFDIAG
NFDPMIPDAE CLKIMCEILS SLQIGDFLVK VNDRRILDGM FAICGVSDSK FRTICSSVDK
LDKVSWEEVK NEMVGEKGLA PEVADRIGDY VQQHGGVSLV EQLLQDPKLS QNKQALEGLG
DLKLLFEYLT LFGIDDKISF DLSLARGLDY YTGVIYEAVL LQTPAQAGEE PLGVGSVAAG
GRYDGLVGMF DPKGRKVPCV GLSIGVERIF SIVEQRLEAL EEKIRTTETQ VLVASAQKKL
LEERLKLVSE LWDAGIKAEL LYKKNPKLLN QLQYCEEAGI PLVAIIGEQE LKDGVIKLRS
VTSREEVDVR REDLVEEIKR RTGQPLCIC
