Full text data of YARS
YARS
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Tyrosine--tRNA ligase, cytoplasmic; 6.1.1.1 (Tyrosyl-tRNA synthetase; TyrRS; Tyrosine--tRNA ligase, cytoplasmic, N-terminally processed)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Tyrosine--tRNA ligase, cytoplasmic; 6.1.1.1 (Tyrosyl-tRNA synthetase; TyrRS; Tyrosine--tRNA ligase, cytoplasmic, N-terminally processed)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P54577
ID SYYC_HUMAN Reviewed; 528 AA.
AC P54577; B3KWK4; D3DPQ4; O43276; Q53EN1;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Tyrosine--tRNA ligase, cytoplasmic;
DE EC=6.1.1.1;
DE AltName: Full=Tyrosyl-tRNA synthetase;
DE Short=TyrRS;
DE Contains:
DE RecName: Full=Tyrosine--tRNA ligase, cytoplasmic, N-terminally processed;
GN Name=YARS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8552597; DOI=10.1073/pnas.93.1.166;
RA Ribas de Pouplana L., Frugier M., Quinn C.L., Schimmel P.;
RT "Evidence that two present-day components needed for the genetic code
RT appeared after nucleated cells separated from eubacteria.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:166-170(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9162081; DOI=10.1074/jbc.272.22.14420;
RA Kleeman T.A., Wei D., Simpson K.L., First E.A.;
RT "Human tyrosyl-tRNA synthetase shares amino acid sequence homology
RT with a putative cytokine.";
RL J. Biol. Chem. 272:14420-14425(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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].
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Bone, and Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 2-16.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [8]
RP PROTEIN SEQUENCE OF 2-16, ACETYLATION AT GLY-2, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (OCT-2004) to UniProtKB.
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1 AND GLY-2, AND MASS
RP SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-197; LYS-206; LYS-474;
RP LYS-482 AND LYS-490, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., 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 [11]
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.,
RA Buerckstuemmer T., 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 [12]
RP X-RAY CRYSTALLOGRAPHY (1.18 ANGSTROMS) OF 1-342, AND SUBUNIT.
RX PubMed=12427973; DOI=10.1073/pnas.242611799;
RA Yang X.-L., Skene R.J., McRee D.E., Schimmel P.;
RT "Crystal structure of a human aminoacyl-tRNA synthetase cytokine.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15369-15374(2002).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-364 IN COMPLEX WITH
RP TYROSINE.
RX PubMed=14671330; DOI=10.1073/pnas.2136794100;
RA Yang X.-L., Otero F.J., Skene R.J., McRee D.E., Schimmel P.,
RA Ribas de Pouplana L.;
RT "Crystal structures that suggest late development of genetic code
RT components for differentiating aromatic side chains.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:15376-15380(2003).
RN [14]
RP SUBCELLULAR LOCATION, VARIANTS CMTDIC 153-VAL--VAL-156 DEL; ARG-41 AND
RP LYS-196, AND CHARACTERIZATION OF VARIANTS CMTDIC ARG-41 AND LYS-196.
RX PubMed=16429158; DOI=10.1038/ng1727;
RA Jordanova A., Irobi J., Thomas F.P., Van Dijck P., Meerschaert K.,
RA Dewil M., Dierick I., Jacobs A., De Vriendt E., Guergueltcheva V.,
RA Rao C.V., Tournev I., Gondim F.A.A., D'Hooghe M., Van Gerwen V.,
RA Callaerts P., Van Den Bosch L., Timmermans J.-P., Robberecht W.,
RA Gettemans J., Thevelein J.M., De Jonghe P., Kremensky I.,
RA Timmerman V.;
RT "Disrupted function and axonal distribution of mutant tyrosyl-tRNA
RT synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.";
RL Nat. Genet. 38:197-202(2006).
CC -!- FUNCTION: Catalyzes the attachment of tyrosine to tRNA(Tyr) in a
CC two-step reaction: tyrosine is first activated by ATP to form Tyr-
CC AMP and then transferred to the acceptor end of tRNA(Tyr) (By
CC similarity).
CC -!- CATALYTIC ACTIVITY: ATP + L-tyrosine + tRNA(Tyr) = AMP +
CC diphosphate + L-tyrosyl-tRNA(Tyr).
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type,
CC C (CMTDIC) [MIM:608323]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. The dominant
CC intermediate type C is characterized by clinical and pathologic
CC features intermediate between demyelinating and axonal peripheral
CC neuropathies, and motor median nerve conduction velocities ranging
CC from 25 to 45 m/sec. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-I aminoacyl-tRNA synthetase
CC family.
CC -!- SIMILARITY: Contains 1 tRNA-binding domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB39406.1; Type=Frameshift; Positions=354;
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DR EMBL; U40714; AAB39406.1; ALT_FRAME; mRNA.
DR EMBL; U89436; AAB88409.1; -; mRNA.
DR EMBL; AK125213; BAG54166.1; -; mRNA.
DR EMBL; AK223608; BAD97328.1; -; mRNA.
DR EMBL; CH471059; EAX07506.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07507.1; -; Genomic_DNA.
DR EMBL; BC001933; AAH01933.1; -; mRNA.
DR EMBL; BC004151; AAH04151.1; -; mRNA.
DR EMBL; BC016689; AAH16689.1; -; mRNA.
DR RefSeq; NP_003671.1; NM_003680.3.
DR UniGene; Hs.213264; -.
DR PDB; 1N3L; X-ray; 1.18 A; A=1-364.
DR PDB; 1NTG; X-ray; 2.21 A; A/B/C/D=359-528.
DR PDB; 1Q11; X-ray; 1.60 A; A=1-364.
DR PDBsum; 1N3L; -.
DR PDBsum; 1NTG; -.
DR PDBsum; 1Q11; -.
DR ProteinModelPortal; P54577; -.
DR SMR; P54577; 4-342, 360-528.
DR IntAct; P54577; 1.
DR STRING; 9606.ENSP00000362576; -.
DR BindingDB; P54577; -.
DR ChEMBL; CHEMBL3179; -.
DR DrugBank; DB00135; L-Tyrosine.
DR PhosphoSite; P54577; -.
DR DMDM; 13638438; -.
DR REPRODUCTION-2DPAGE; IPI00007074; -.
DR PaxDb; P54577; -.
DR PeptideAtlas; P54577; -.
DR PRIDE; P54577; -.
DR DNASU; 8565; -.
DR Ensembl; ENST00000373477; ENSP00000362576; ENSG00000134684.
DR GeneID; 8565; -.
DR KEGG; hsa:8565; -.
DR UCSC; uc001bvy.1; human.
DR CTD; 8565; -.
DR GeneCards; GC01M033240; -.
DR HGNC; HGNC:12840; YARS.
DR HPA; HPA017936; -.
DR HPA; HPA018950; -.
DR HPA; HPA018954; -.
DR MIM; 603623; gene.
DR MIM; 608323; phenotype.
DR neXtProt; NX_P54577; -.
DR Orphanet; 100045; Autosomal dominant intermediate Charcot-Marie-Tooth disease type C.
DR PharmGKB; PA37431; -.
DR eggNOG; COG0162; -.
DR HOGENOM; HOG000228237; -.
DR HOVERGEN; HBG080113; -.
DR InParanoid; P54577; -.
DR KO; K01866; -.
DR OMA; NRQVEPL; -.
DR OrthoDB; EOG79CXZ2; -.
DR PhylomeDB; P54577; -.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; YARS; human.
DR EvolutionaryTrace; P54577; -.
DR GeneWiki; YARS; -.
DR GenomeRNAi; 8565; -.
DR NextBio; 32113; -.
DR PMAP-CutDB; P54577; -.
DR PRO; PR:P54577; -.
DR Bgee; P54577; -.
DR CleanEx; HS_YARS; -.
DR Genevestigator; P54577; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005153; F:interleukin-8 receptor binding; TAS:ProtInc.
DR GO; GO:0004871; F:signal transducer activity; NAS:ProtInc.
DR GO; GO:0000049; F:tRNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004831; F:tyrosine-tRNA ligase activity; TAS:Reactome.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0006437; P:tyrosyl-tRNA aminoacylation; TAS:ProtInc.
DR Gene3D; 2.40.50.140; -; 1.
DR Gene3D; 3.40.50.620; -; 1.
DR InterPro; IPR002305; aa-tRNA-synth_Ic.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR InterPro; IPR002547; tRNA-bd_dom.
DR InterPro; IPR002307; Tyr-tRNA-ligase.
DR InterPro; IPR023617; Tyr-tRNA-ligase_arc/euk-type.
DR PANTHER; PTHR11946:SF8; PTHR11946:SF8; 1.
DR Pfam; PF00579; tRNA-synt_1b; 1.
DR Pfam; PF01588; tRNA_bind; 1.
DR PRINTS; PR01040; TRNASYNTHTYR.
DR SUPFAM; SSF50249; SSF50249; 1.
DR TIGRFAMs; TIGR00234; tyrS; 1.
DR PROSITE; PS00178; AA_TRNA_LIGASE_I; FALSE_NEG.
DR PROSITE; PS50886; TRBD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Charcot-Marie-Tooth disease; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Ligase; Neuropathy;
KW Nucleotide-binding; Polymorphism; Protein biosynthesis;
KW Reference proteome; RNA-binding; tRNA-binding.
FT CHAIN 1 528 Tyrosine--tRNA ligase, cytoplasmic.
FT /FTId=PRO_0000423285.
FT INIT_MET 1 1 Removed; alternate.
FT CHAIN 2 528 Tyrosine--tRNA ligase, cytoplasmic, N-
FT terminally processed.
FT /FTId=PRO_0000055673.
FT DOMAIN 364 468 tRNA-binding.
FT MOTIF 44 52 "HIGH" region.
FT MOTIF 222 226 "KMSKS" region.
FT BINDING 39 39 Tyrosine.
FT BINDING 166 166 Tyrosine.
FT BINDING 170 170 Tyrosine.
FT BINDING 173 173 Tyrosine.
FT BINDING 188 188 Tyrosine.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 2 2 N-acetylglycine; in Tyrosine--tRNA
FT ligase, cytoplasmic, N-terminally
FT processed.
FT MOD_RES 197 197 N6-acetyllysine.
FT MOD_RES 206 206 N6-acetyllysine.
FT MOD_RES 474 474 N6-acetyllysine.
FT MOD_RES 482 482 N6-acetyllysine.
FT MOD_RES 490 490 N6-acetyllysine.
FT VARIANT 41 41 G -> R (in CMTDIC; partial loss of
FT activity).
FT /FTId=VAR_026681.
FT VARIANT 153 156 Missing (in CMTDIC).
FT /FTId=VAR_026682.
FT VARIANT 170 170 Q -> H (in dbSNP:rs2128600).
FT /FTId=VAR_026683.
FT VARIANT 196 196 E -> K (in CMTDIC; partial loss of
FT activity).
FT /FTId=VAR_026684.
FT CONFLICT 143 143 H -> R (in Ref. 4; BAD97328).
FT HELIX 7 15
FT STRAND 19 22
FT HELIX 24 31
FT STRAND 37 42
FT HELIX 50 52
FT HELIX 53 64
FT STRAND 68 73
FT HELIX 75 80
FT TURN 81 84
FT HELIX 87 108
FT STRAND 115 119
FT HELIX 120 122
FT TURN 123 125
FT HELIX 127 137
FT HELIX 142 148
FT TURN 149 152
FT HELIX 161 176
FT STRAND 180 185
FT HELIX 186 188
FT HELIX 189 198
FT HELIX 199 202
FT STRAND 208 212
FT HELIX 238 246
FT STRAND 247 249
FT HELIX 259 266
FT TURN 267 273
FT STRAND 275 277
FT HELIX 281 283
FT STRAND 287 291
FT HELIX 292 300
FT HELIX 306 327
FT HELIX 331 340
FT HELIX 365 367
FT STRAND 370 380
FT STRAND 388 393
FT STRAND 395 398
FT STRAND 400 405
FT TURN 407 409
FT HELIX 412 414
FT TURN 415 417
FT STRAND 419 423
FT STRAND 429 431
FT STRAND 434 436
FT STRAND 442 454
FT STRAND 466 469
FT STRAND 479 481
FT HELIX 483 485
FT HELIX 487 492
FT STRAND 495 497
FT STRAND 501 505
FT STRAND 508 512
FT STRAND 526 528
SQ SEQUENCE 528 AA; 59143 MW; 00C7E88843905780 CRC64;
MGDAPSPEEK LHLITRNLQE VLGEEKLKEI LKERELKIYW GTATTGKPHV AYFVPMSKIA
DFLKAGCEVT ILFADLHAYL DNMKAPWELL ELRVSYYENV IKAMLESIGV PLEKLKFIKG
TDYQLSKEYT LDVYRLSSVV TQHDSKKAGA EVVKQVEHPL LSGLLYPGLQ ALDEEYLKVD
AQFGGIDQRK IFTFAEKYLP ALGYSKRVHL MNPMVPGLTG SKMSSSEEES KIDLLDRKED
VKKKLKKAFC EPGNVENNGV LSFIKHVLFP LKSEFVILRD EKWGGNKTYT AYVDLEKDFA
AEVVHPGDLK NSVEVALNKL LDPIREKFNT PALKKLASAA YPDPSKQKPM AKGPAKNSEP
EEVIPSRLDI RVGKIITVEK HPDADSLYVE KIDVGEAEPR TVVSGLVQFV PKEELQDRLV
VVLCNLKPQK MRGVESQGML LCASIEGINR QVEPLDPPAG SAPGEHVFVK GYEKGQPDEE
LKPKKKVFEK LQADFKISEE CIAQWKQTNF MTKLGSISCK SLKGGNIS
//
ID SYYC_HUMAN Reviewed; 528 AA.
AC P54577; B3KWK4; D3DPQ4; O43276; Q53EN1;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Tyrosine--tRNA ligase, cytoplasmic;
DE EC=6.1.1.1;
DE AltName: Full=Tyrosyl-tRNA synthetase;
DE Short=TyrRS;
DE Contains:
DE RecName: Full=Tyrosine--tRNA ligase, cytoplasmic, N-terminally processed;
GN Name=YARS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8552597; DOI=10.1073/pnas.93.1.166;
RA Ribas de Pouplana L., Frugier M., Quinn C.L., Schimmel P.;
RT "Evidence that two present-day components needed for the genetic code
RT appeared after nucleated cells separated from eubacteria.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:166-170(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9162081; DOI=10.1074/jbc.272.22.14420;
RA Kleeman T.A., Wei D., Simpson K.L., First E.A.;
RT "Human tyrosyl-tRNA synthetase shares amino acid sequence homology
RT with a putative cytokine.";
RL J. Biol. Chem. 272:14420-14425(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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].
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Bone, and Lung;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 2-16.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [8]
RP PROTEIN SEQUENCE OF 2-16, ACETYLATION AT GLY-2, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (OCT-2004) to UniProtKB.
RN [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1 AND GLY-2, AND MASS
RP SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-197; LYS-206; LYS-474;
RP LYS-482 AND LYS-490, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., 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 [11]
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.,
RA Buerckstuemmer T., 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 [12]
RP X-RAY CRYSTALLOGRAPHY (1.18 ANGSTROMS) OF 1-342, AND SUBUNIT.
RX PubMed=12427973; DOI=10.1073/pnas.242611799;
RA Yang X.-L., Skene R.J., McRee D.E., Schimmel P.;
RT "Crystal structure of a human aminoacyl-tRNA synthetase cytokine.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15369-15374(2002).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 1-364 IN COMPLEX WITH
RP TYROSINE.
RX PubMed=14671330; DOI=10.1073/pnas.2136794100;
RA Yang X.-L., Otero F.J., Skene R.J., McRee D.E., Schimmel P.,
RA Ribas de Pouplana L.;
RT "Crystal structures that suggest late development of genetic code
RT components for differentiating aromatic side chains.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:15376-15380(2003).
RN [14]
RP SUBCELLULAR LOCATION, VARIANTS CMTDIC 153-VAL--VAL-156 DEL; ARG-41 AND
RP LYS-196, AND CHARACTERIZATION OF VARIANTS CMTDIC ARG-41 AND LYS-196.
RX PubMed=16429158; DOI=10.1038/ng1727;
RA Jordanova A., Irobi J., Thomas F.P., Van Dijck P., Meerschaert K.,
RA Dewil M., Dierick I., Jacobs A., De Vriendt E., Guergueltcheva V.,
RA Rao C.V., Tournev I., Gondim F.A.A., D'Hooghe M., Van Gerwen V.,
RA Callaerts P., Van Den Bosch L., Timmermans J.-P., Robberecht W.,
RA Gettemans J., Thevelein J.M., De Jonghe P., Kremensky I.,
RA Timmerman V.;
RT "Disrupted function and axonal distribution of mutant tyrosyl-tRNA
RT synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy.";
RL Nat. Genet. 38:197-202(2006).
CC -!- FUNCTION: Catalyzes the attachment of tyrosine to tRNA(Tyr) in a
CC two-step reaction: tyrosine is first activated by ATP to form Tyr-
CC AMP and then transferred to the acceptor end of tRNA(Tyr) (By
CC similarity).
CC -!- CATALYTIC ACTIVITY: ATP + L-tyrosine + tRNA(Tyr) = AMP +
CC diphosphate + L-tyrosyl-tRNA(Tyr).
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- DISEASE: Charcot-Marie-Tooth disease, dominant, intermediate type,
CC C (CMTDIC) [MIM:608323]: A form of Charcot-Marie-Tooth disease, a
CC disorder of the peripheral nervous system, characterized by
CC progressive weakness and atrophy, initially of the peroneal
CC muscles and later of the distal muscles of the arms. The dominant
CC intermediate type C is characterized by clinical and pathologic
CC features intermediate between demyelinating and axonal peripheral
CC neuropathies, and motor median nerve conduction velocities ranging
CC from 25 to 45 m/sec. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-I aminoacyl-tRNA synthetase
CC family.
CC -!- SIMILARITY: Contains 1 tRNA-binding domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB39406.1; Type=Frameshift; Positions=354;
CC -----------------------------------------------------------------------
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DR EMBL; U40714; AAB39406.1; ALT_FRAME; mRNA.
DR EMBL; U89436; AAB88409.1; -; mRNA.
DR EMBL; AK125213; BAG54166.1; -; mRNA.
DR EMBL; AK223608; BAD97328.1; -; mRNA.
DR EMBL; CH471059; EAX07506.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07507.1; -; Genomic_DNA.
DR EMBL; BC001933; AAH01933.1; -; mRNA.
DR EMBL; BC004151; AAH04151.1; -; mRNA.
DR EMBL; BC016689; AAH16689.1; -; mRNA.
DR RefSeq; NP_003671.1; NM_003680.3.
DR UniGene; Hs.213264; -.
DR PDB; 1N3L; X-ray; 1.18 A; A=1-364.
DR PDB; 1NTG; X-ray; 2.21 A; A/B/C/D=359-528.
DR PDB; 1Q11; X-ray; 1.60 A; A=1-364.
DR PDBsum; 1N3L; -.
DR PDBsum; 1NTG; -.
DR PDBsum; 1Q11; -.
DR ProteinModelPortal; P54577; -.
DR SMR; P54577; 4-342, 360-528.
DR IntAct; P54577; 1.
DR STRING; 9606.ENSP00000362576; -.
DR BindingDB; P54577; -.
DR ChEMBL; CHEMBL3179; -.
DR DrugBank; DB00135; L-Tyrosine.
DR PhosphoSite; P54577; -.
DR DMDM; 13638438; -.
DR REPRODUCTION-2DPAGE; IPI00007074; -.
DR PaxDb; P54577; -.
DR PeptideAtlas; P54577; -.
DR PRIDE; P54577; -.
DR DNASU; 8565; -.
DR Ensembl; ENST00000373477; ENSP00000362576; ENSG00000134684.
DR GeneID; 8565; -.
DR KEGG; hsa:8565; -.
DR UCSC; uc001bvy.1; human.
DR CTD; 8565; -.
DR GeneCards; GC01M033240; -.
DR HGNC; HGNC:12840; YARS.
DR HPA; HPA017936; -.
DR HPA; HPA018950; -.
DR HPA; HPA018954; -.
DR MIM; 603623; gene.
DR MIM; 608323; phenotype.
DR neXtProt; NX_P54577; -.
DR Orphanet; 100045; Autosomal dominant intermediate Charcot-Marie-Tooth disease type C.
DR PharmGKB; PA37431; -.
DR eggNOG; COG0162; -.
DR HOGENOM; HOG000228237; -.
DR HOVERGEN; HBG080113; -.
DR InParanoid; P54577; -.
DR KO; K01866; -.
DR OMA; NRQVEPL; -.
DR OrthoDB; EOG79CXZ2; -.
DR PhylomeDB; P54577; -.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; YARS; human.
DR EvolutionaryTrace; P54577; -.
DR GeneWiki; YARS; -.
DR GenomeRNAi; 8565; -.
DR NextBio; 32113; -.
DR PMAP-CutDB; P54577; -.
DR PRO; PR:P54577; -.
DR Bgee; P54577; -.
DR CleanEx; HS_YARS; -.
DR Genevestigator; P54577; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; TAS:ProtInc.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005153; F:interleukin-8 receptor binding; TAS:ProtInc.
DR GO; GO:0004871; F:signal transducer activity; NAS:ProtInc.
DR GO; GO:0000049; F:tRNA binding; IEA:UniProtKB-KW.
DR GO; GO:0004831; F:tyrosine-tRNA ligase activity; TAS:Reactome.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:0006437; P:tyrosyl-tRNA aminoacylation; TAS:ProtInc.
DR Gene3D; 2.40.50.140; -; 1.
DR Gene3D; 3.40.50.620; -; 1.
DR InterPro; IPR002305; aa-tRNA-synth_Ic.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR InterPro; IPR002547; tRNA-bd_dom.
DR InterPro; IPR002307; Tyr-tRNA-ligase.
DR InterPro; IPR023617; Tyr-tRNA-ligase_arc/euk-type.
DR PANTHER; PTHR11946:SF8; PTHR11946:SF8; 1.
DR Pfam; PF00579; tRNA-synt_1b; 1.
DR Pfam; PF01588; tRNA_bind; 1.
DR PRINTS; PR01040; TRNASYNTHTYR.
DR SUPFAM; SSF50249; SSF50249; 1.
DR TIGRFAMs; TIGR00234; tyrS; 1.
DR PROSITE; PS00178; AA_TRNA_LIGASE_I; FALSE_NEG.
DR PROSITE; PS50886; TRBD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Charcot-Marie-Tooth disease; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Ligase; Neuropathy;
KW Nucleotide-binding; Polymorphism; Protein biosynthesis;
KW Reference proteome; RNA-binding; tRNA-binding.
FT CHAIN 1 528 Tyrosine--tRNA ligase, cytoplasmic.
FT /FTId=PRO_0000423285.
FT INIT_MET 1 1 Removed; alternate.
FT CHAIN 2 528 Tyrosine--tRNA ligase, cytoplasmic, N-
FT terminally processed.
FT /FTId=PRO_0000055673.
FT DOMAIN 364 468 tRNA-binding.
FT MOTIF 44 52 "HIGH" region.
FT MOTIF 222 226 "KMSKS" region.
FT BINDING 39 39 Tyrosine.
FT BINDING 166 166 Tyrosine.
FT BINDING 170 170 Tyrosine.
FT BINDING 173 173 Tyrosine.
FT BINDING 188 188 Tyrosine.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 2 2 N-acetylglycine; in Tyrosine--tRNA
FT ligase, cytoplasmic, N-terminally
FT processed.
FT MOD_RES 197 197 N6-acetyllysine.
FT MOD_RES 206 206 N6-acetyllysine.
FT MOD_RES 474 474 N6-acetyllysine.
FT MOD_RES 482 482 N6-acetyllysine.
FT MOD_RES 490 490 N6-acetyllysine.
FT VARIANT 41 41 G -> R (in CMTDIC; partial loss of
FT activity).
FT /FTId=VAR_026681.
FT VARIANT 153 156 Missing (in CMTDIC).
FT /FTId=VAR_026682.
FT VARIANT 170 170 Q -> H (in dbSNP:rs2128600).
FT /FTId=VAR_026683.
FT VARIANT 196 196 E -> K (in CMTDIC; partial loss of
FT activity).
FT /FTId=VAR_026684.
FT CONFLICT 143 143 H -> R (in Ref. 4; BAD97328).
FT HELIX 7 15
FT STRAND 19 22
FT HELIX 24 31
FT STRAND 37 42
FT HELIX 50 52
FT HELIX 53 64
FT STRAND 68 73
FT HELIX 75 80
FT TURN 81 84
FT HELIX 87 108
FT STRAND 115 119
FT HELIX 120 122
FT TURN 123 125
FT HELIX 127 137
FT HELIX 142 148
FT TURN 149 152
FT HELIX 161 176
FT STRAND 180 185
FT HELIX 186 188
FT HELIX 189 198
FT HELIX 199 202
FT STRAND 208 212
FT HELIX 238 246
FT STRAND 247 249
FT HELIX 259 266
FT TURN 267 273
FT STRAND 275 277
FT HELIX 281 283
FT STRAND 287 291
FT HELIX 292 300
FT HELIX 306 327
FT HELIX 331 340
FT HELIX 365 367
FT STRAND 370 380
FT STRAND 388 393
FT STRAND 395 398
FT STRAND 400 405
FT TURN 407 409
FT HELIX 412 414
FT TURN 415 417
FT STRAND 419 423
FT STRAND 429 431
FT STRAND 434 436
FT STRAND 442 454
FT STRAND 466 469
FT STRAND 479 481
FT HELIX 483 485
FT HELIX 487 492
FT STRAND 495 497
FT STRAND 501 505
FT STRAND 508 512
FT STRAND 526 528
SQ SEQUENCE 528 AA; 59143 MW; 00C7E88843905780 CRC64;
MGDAPSPEEK LHLITRNLQE VLGEEKLKEI LKERELKIYW GTATTGKPHV AYFVPMSKIA
DFLKAGCEVT ILFADLHAYL DNMKAPWELL ELRVSYYENV IKAMLESIGV PLEKLKFIKG
TDYQLSKEYT LDVYRLSSVV TQHDSKKAGA EVVKQVEHPL LSGLLYPGLQ ALDEEYLKVD
AQFGGIDQRK IFTFAEKYLP ALGYSKRVHL MNPMVPGLTG SKMSSSEEES KIDLLDRKED
VKKKLKKAFC EPGNVENNGV LSFIKHVLFP LKSEFVILRD EKWGGNKTYT AYVDLEKDFA
AEVVHPGDLK NSVEVALNKL LDPIREKFNT PALKKLASAA YPDPSKQKPM AKGPAKNSEP
EEVIPSRLDI RVGKIITVEK HPDADSLYVE KIDVGEAEPR TVVSGLVQFV PKEELQDRLV
VVLCNLKPQK MRGVESQGML LCASIEGINR QVEPLDPPAG SAPGEHVFVK GYEKGQPDEE
LKPKKKVFEK LQADFKISEE CIAQWKQTNF MTKLGSISCK SLKGGNIS
//
MIM
603623
*RECORD*
*FIELD* NO
603623
*FIELD* TI
*603623 TYROSYL-tRNA SYNTHETASE; YARS
;;TYRRS;;
YTS;;
YRS
*FIELD* TX
CLONING
Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their
read morecognate amino acid. Because of their central role in linking amino acids
with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases
are thought to be among the first proteins that appeared in evolution.
Kleeman et al. (1997) cloned cDNAs encoding tyrosyl-tRNA synthetase
(YARS) from several different human cDNA libraries. The YARS cDNA
sequence encodes a 528-amino acid polypeptide. Sequence analysis
revealed that the carboxyl end of the protein contains a region with 49%
identity to endothelial monocyte-activating polypeptide II (EMAP II;
603605).
GENE FUNCTION
While native human tyrosyl-tRNA synthetase is inactive as a
cell-signaling molecule, it can be split into 2 distinct cytokines. The
enzyme is secreted under apoptotic conditions in culture, where it is
cleaved into an N-terminal fragment that harbors the catalytic site and
into a C-terminal fragment found only in the mammalian enzyme. The
N-terminal fragment is an interleukin-8 (IL8; 146930)-like cytokine,
whereas the released C-terminal fragment is an EMAP II-like cytokine.
Wakasugi and Schimmel (1999) found that the cytokine activities of split
human tyrosyl-tRNA synthetase depend on highly differentiated motifs
that are idiosyncratic to the mammalian system.
Jordanova et al. (2006) determined that YARS is expressed ubiquitously,
including in brain and spinal cord.
MAPPING
The YARS gene resides on chromosome 1p35-p34 (Jordanova et al., 2006).
MOLECULAR GENETICS
Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a
genetic and phenotypic variant of classic CMT characterized by
intermediate nerve conduction velocities and histologic evidence of both
axonal and demyelinating features. In an American family with DI-CMTC
(608323), Jordanova et al. (2006) identified a heterozygous transition
in exon 2 of the YARS gene (G41R; 603623.0001), and in a Bulgarian
family they found a heterozygous transition in exon 5 (E196K;
603623.0002). Furthermore, they identified a 12-bp in-frame deletion in
exon 4 in an affected individual from Belgium (603623.0003).
EVOLUTION
Ribas de Pouplana et al. (1996) performed multiple sequence alignments
for the tRNA synthetases. They concluded that tyrosyl-tRNA synthetase
and tryptophanyl-tRNA synthetase (191050) may have diverged after the
separation of eukaryotes from eubacteria.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C
YARS, GLY41ARG
In a North American family, Jordanova et al. (2006) found a heterozygous
121G-A transition in exon 2 of the YARS gene, causing a missense amino
acid change (G41R), as the cause of dominant intermediate
Charcot-Marie-Tooth neuropathy (608323).
.0002
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C
YARS, GLU196LYS
In a Bulgarian family with dominant intermediate Charcot-Marie-Tooth
neuropathy (608323), Jordanova et al. (2006) found a 586G-A transition
in exon 5 of the YARS gene that resulted in a glu196-to-lys (E196K)
mutation.
.0003
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C
YARS, 12-BP DEL
In an individual from Belgium with dominant intermediate
Charcot-Marie-Tooth neuropathy (608323), Jordanova et al. (2006) found a
12-bp in-frame deletion (153-156delVKQV) in exon 4 of the YARS gene.
Mutation analysis and genotyping of her asymptomatic parents showed that
this mutation occurred de novo.
*FIELD* SA
Jordanova et al. (2003)
*FIELD* RF
1. Jordanova, A.; Irobi, J.; Thomas, F. P.; Van Dijck, P.; Meerschaert,
K.; Dewil, M.; Dierick, I.; Jacobs, A.; De Vriendt, E.; Guergueltcheva,
V.; Rao, C. V.; Tournev, I.; and 12 others: Disrupted function
and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant
intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38: 197-202,
2006.
2. Jordanova, A.; Thomas, F. P.; Guergueltcheva, V.; Tournev, I.;
Gondim, F. A. A.; Ishpekova, B.; De Vriendt, E.; Jacobs, A.; Litvinenko,
I.; Ivanova, N.; Buzhov, B.; De Jonghe, P.; Kremensky, I.; Timmerman,
V.: Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome
1p34-p35. Am. J. Hum. Genet. 73: 1423-1430, 2003.
3. Kleeman, T. A.; Wei, D.; Simpson, K. L.; First, E. A.: Human tyrosyl-tRNA
synthetase shares amino acid sequence homology with a putative cytokine. J.
Biol. Chem. 272: 14420-14425, 1997.
4. Ribas de Pouplana, L.; Frugier, M.; Quinn, C. L.; Schimmel, P.
: Evidence that two present-day components needed for the genetic
code appeared after nucleated cells separated from eubacteria. Proc.
Nat. Acad. Sci. 93: 166-170, 1996.
5. Wakasugi, K.; Schimmel, P.: Highly differentiated motifs responsible
for two cytokine activities of a split human tRNA synthetase. J.
Biol. Chem 274: 23155-23159, 1999.
*FIELD* CN
Victor A. McKusick - updated: 2/7/2006
Victor A. McKusick - updated: 10/11/1999
*FIELD* CD
Jennifer P. Macke: 3/10/1999
*FIELD* ED
alopez: 02/10/2006
terry: 2/7/2006
mgross: 10/11/1999
mgross: 3/16/1999
mgross: 3/10/1999
*RECORD*
*FIELD* NO
603623
*FIELD* TI
*603623 TYROSYL-tRNA SYNTHETASE; YARS
;;TYRRS;;
YTS;;
YRS
*FIELD* TX
CLONING
Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their
read morecognate amino acid. Because of their central role in linking amino acids
with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases
are thought to be among the first proteins that appeared in evolution.
Kleeman et al. (1997) cloned cDNAs encoding tyrosyl-tRNA synthetase
(YARS) from several different human cDNA libraries. The YARS cDNA
sequence encodes a 528-amino acid polypeptide. Sequence analysis
revealed that the carboxyl end of the protein contains a region with 49%
identity to endothelial monocyte-activating polypeptide II (EMAP II;
603605).
GENE FUNCTION
While native human tyrosyl-tRNA synthetase is inactive as a
cell-signaling molecule, it can be split into 2 distinct cytokines. The
enzyme is secreted under apoptotic conditions in culture, where it is
cleaved into an N-terminal fragment that harbors the catalytic site and
into a C-terminal fragment found only in the mammalian enzyme. The
N-terminal fragment is an interleukin-8 (IL8; 146930)-like cytokine,
whereas the released C-terminal fragment is an EMAP II-like cytokine.
Wakasugi and Schimmel (1999) found that the cytokine activities of split
human tyrosyl-tRNA synthetase depend on highly differentiated motifs
that are idiosyncratic to the mammalian system.
Jordanova et al. (2006) determined that YARS is expressed ubiquitously,
including in brain and spinal cord.
MAPPING
The YARS gene resides on chromosome 1p35-p34 (Jordanova et al., 2006).
MOLECULAR GENETICS
Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a
genetic and phenotypic variant of classic CMT characterized by
intermediate nerve conduction velocities and histologic evidence of both
axonal and demyelinating features. In an American family with DI-CMTC
(608323), Jordanova et al. (2006) identified a heterozygous transition
in exon 2 of the YARS gene (G41R; 603623.0001), and in a Bulgarian
family they found a heterozygous transition in exon 5 (E196K;
603623.0002). Furthermore, they identified a 12-bp in-frame deletion in
exon 4 in an affected individual from Belgium (603623.0003).
EVOLUTION
Ribas de Pouplana et al. (1996) performed multiple sequence alignments
for the tRNA synthetases. They concluded that tyrosyl-tRNA synthetase
and tryptophanyl-tRNA synthetase (191050) may have diverged after the
separation of eukaryotes from eubacteria.
*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C
YARS, GLY41ARG
In a North American family, Jordanova et al. (2006) found a heterozygous
121G-A transition in exon 2 of the YARS gene, causing a missense amino
acid change (G41R), as the cause of dominant intermediate
Charcot-Marie-Tooth neuropathy (608323).
.0002
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C
YARS, GLU196LYS
In a Bulgarian family with dominant intermediate Charcot-Marie-Tooth
neuropathy (608323), Jordanova et al. (2006) found a 586G-A transition
in exon 5 of the YARS gene that resulted in a glu196-to-lys (E196K)
mutation.
.0003
CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C
YARS, 12-BP DEL
In an individual from Belgium with dominant intermediate
Charcot-Marie-Tooth neuropathy (608323), Jordanova et al. (2006) found a
12-bp in-frame deletion (153-156delVKQV) in exon 4 of the YARS gene.
Mutation analysis and genotyping of her asymptomatic parents showed that
this mutation occurred de novo.
*FIELD* SA
Jordanova et al. (2003)
*FIELD* RF
1. Jordanova, A.; Irobi, J.; Thomas, F. P.; Van Dijck, P.; Meerschaert,
K.; Dewil, M.; Dierick, I.; Jacobs, A.; De Vriendt, E.; Guergueltcheva,
V.; Rao, C. V.; Tournev, I.; and 12 others: Disrupted function
and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant
intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38: 197-202,
2006.
2. Jordanova, A.; Thomas, F. P.; Guergueltcheva, V.; Tournev, I.;
Gondim, F. A. A.; Ishpekova, B.; De Vriendt, E.; Jacobs, A.; Litvinenko,
I.; Ivanova, N.; Buzhov, B.; De Jonghe, P.; Kremensky, I.; Timmerman,
V.: Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome
1p34-p35. Am. J. Hum. Genet. 73: 1423-1430, 2003.
3. Kleeman, T. A.; Wei, D.; Simpson, K. L.; First, E. A.: Human tyrosyl-tRNA
synthetase shares amino acid sequence homology with a putative cytokine. J.
Biol. Chem. 272: 14420-14425, 1997.
4. Ribas de Pouplana, L.; Frugier, M.; Quinn, C. L.; Schimmel, P.
: Evidence that two present-day components needed for the genetic
code appeared after nucleated cells separated from eubacteria. Proc.
Nat. Acad. Sci. 93: 166-170, 1996.
5. Wakasugi, K.; Schimmel, P.: Highly differentiated motifs responsible
for two cytokine activities of a split human tRNA synthetase. J.
Biol. Chem 274: 23155-23159, 1999.
*FIELD* CN
Victor A. McKusick - updated: 2/7/2006
Victor A. McKusick - updated: 10/11/1999
*FIELD* CD
Jennifer P. Macke: 3/10/1999
*FIELD* ED
alopez: 02/10/2006
terry: 2/7/2006
mgross: 10/11/1999
mgross: 3/16/1999
mgross: 3/10/1999
MIM
608323
*RECORD*
*FIELD* NO
608323
*FIELD* TI
#608323 CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C; CMTDIC
;;CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE C;;
read moreDI-CMTC
*FIELD* TX
A number sign (#) is used with this entry because of evidence that type
C dominant intermediate Charcot-Marie-Tooth neuropathy, distinguished by
mapping to 1p35-p34, is caused by mutations in tyrosyl-tRNA synthetase
(YARS; 603623).
For a phenotypic description and a discussion of genetic heterogeneity
of dominant intermediate CMT neuropathy, see CMTDIB (606482).
CLINICAL FEATURES
Jordanova et al. (2003) reported 2 unrelated families with autosomal
dominant intermediate Charcot-Marie-Tooth disease. One family, American
with German and Polish roots, contained 15 affected individuals over 4
generations. Age at onset was in the first and second decades, with
distal leg and arm weakness and numbness. Motor nerve conduction
velocities (NCV) ranged from 30-40 m/s. Sural nerve biopsies showed
clusters of regenerating fibers and reduction in fiber density and
myelin thickness, but no onion bulb formations. The second family, from
Bulgaria, had 19 affected members over 7 generations traced back to
1850. Disease onset ranged from 7 to 59 years, and motor symptoms and
lower limb involvement predominated. Motor NCVs ranged from 33 m/s to
normal.
MAPPING
Jordanova et al. (2003) performed a genomewide search in 2 unrelated
families with DI-CMT and detected linkage within a 6.3-cM region on
chromosome 1p35 (maximum lod scores for the 2 families were 5.39 and
6.81 at marker D1S233). The 2 families did not share a common
disease-associated haplotype. The functional and positional candidate
genes SDC3 (186357) and LAPTM5 (601476) were excluded for pathogenic
mutations.
MOLECULAR GENETICS
In the American family described by Jordanova et al. (2003), Jordanova
et al. (2006) found a missense mutation in the YARS gene (G41R;
603623.0001). In the Bulgarian family they found a different missense
mutation (E196K; 603623.0002), and in an affected individual from
Belgium they found an in-frame deletion (603623.0003). Biochemical
experiments and genetic complementation in yeast showed partial loss of
aminoacylation activity of the mutant proteins, and mutations in YARS,
or in its yeast ortholog TYS1, reduced yeast growth. YARS localized to
axonal termini in differentiating primary motor neuron and neuroblastoma
cultures. This specific distribution is significantly reduced in cells
expressing mutant YARS proteins. YARS was the second aminoacyl-tRNA
synthetase found to be involved in Charcot-Marie-Tooth disease, thereby
linking protein-synthesizing complexes with neurodegeneration. Dominant
mutations in GARS, which encodes glycyl-tRNA synthetase (600287), had
been found in type 2D Charcot-Marie-Tooth disease (601472) and in distal
spinal muscular atrophy type VA (DSMAVA; 600794).
*FIELD* RF
1. Jordanova, A.; Irobi, J.; Thomas, F. P.; Van Dijck, P.; Meerschaert,
K.; Dewil, M.; Dierick, I.; Jacobs, A.; De Vriendt, E.; Guergueltcheva,
V.; Rao, C. V.; Tournev, I.; and 12 others: Disrupted function
and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant
intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38: 197-202,
2006.
2. Jordanova, A.; Thomas, F. P.; Guergueltcheva, V.; Tournev, I.;
Gondim, F. A. A.; Ishpekova, B.; De Vriendt, E.; Jacobs, A.; Litvinenko,
I.; Ivanova, N.; Buzhov, B.; De Jonghe, P.; Kremensky, I.; Timmerman,
V.: Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome
1p34-p35. Am. J. Hum. Genet. 73: 1423-1430, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Foot deformities may occur
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Upper limb involvement may occur later;
Distal sensory impairment;
Low to normal range of nerve conduction velocity (NCV) (30-40 m/s);
Axonal regeneration on nerve biopsy;
Decreased nerve fiber density and thickness;
No onion bulb formations
MISCELLANEOUS:
Variable age of onset (7-59 years);
Begins in feet and legs (peroneal distribution);
Features intermediate between demyelinating CMT and axonal CMT;
Genetic heterogeneity (see CMTDIA 606483)
MOLECULAR BASIS:
Caused by mutation in the tyrosyl-tRNA synthetase gene (YARS, 603623.0001)
*FIELD* CN
Joanna S. Amberger - updated: 03/19/2010
*FIELD* CD
Cassandra L. Kniffin: 12/9/2003
*FIELD* ED
joanna: 03/19/2010
joanna: 1/13/2004
ckniffin: 12/11/2003
*FIELD* CN
Victor A. McKusick - updated: 2/7/2006
*FIELD* CD
Cassandra L. Kniffin: 12/5/2003
*FIELD* ED
carol: 08/01/2012
wwang: 5/11/2010
alopez: 2/10/2006
terry: 2/7/2006
alopez: 3/17/2004
carol: 12/12/2003
ckniffin: 12/8/2003
*RECORD*
*FIELD* NO
608323
*FIELD* TI
#608323 CHARCOT-MARIE-TOOTH DISEASE, DOMINANT INTERMEDIATE C; CMTDIC
;;CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE C;;
read moreDI-CMTC
*FIELD* TX
A number sign (#) is used with this entry because of evidence that type
C dominant intermediate Charcot-Marie-Tooth neuropathy, distinguished by
mapping to 1p35-p34, is caused by mutations in tyrosyl-tRNA synthetase
(YARS; 603623).
For a phenotypic description and a discussion of genetic heterogeneity
of dominant intermediate CMT neuropathy, see CMTDIB (606482).
CLINICAL FEATURES
Jordanova et al. (2003) reported 2 unrelated families with autosomal
dominant intermediate Charcot-Marie-Tooth disease. One family, American
with German and Polish roots, contained 15 affected individuals over 4
generations. Age at onset was in the first and second decades, with
distal leg and arm weakness and numbness. Motor nerve conduction
velocities (NCV) ranged from 30-40 m/s. Sural nerve biopsies showed
clusters of regenerating fibers and reduction in fiber density and
myelin thickness, but no onion bulb formations. The second family, from
Bulgaria, had 19 affected members over 7 generations traced back to
1850. Disease onset ranged from 7 to 59 years, and motor symptoms and
lower limb involvement predominated. Motor NCVs ranged from 33 m/s to
normal.
MAPPING
Jordanova et al. (2003) performed a genomewide search in 2 unrelated
families with DI-CMT and detected linkage within a 6.3-cM region on
chromosome 1p35 (maximum lod scores for the 2 families were 5.39 and
6.81 at marker D1S233). The 2 families did not share a common
disease-associated haplotype. The functional and positional candidate
genes SDC3 (186357) and LAPTM5 (601476) were excluded for pathogenic
mutations.
MOLECULAR GENETICS
In the American family described by Jordanova et al. (2003), Jordanova
et al. (2006) found a missense mutation in the YARS gene (G41R;
603623.0001). In the Bulgarian family they found a different missense
mutation (E196K; 603623.0002), and in an affected individual from
Belgium they found an in-frame deletion (603623.0003). Biochemical
experiments and genetic complementation in yeast showed partial loss of
aminoacylation activity of the mutant proteins, and mutations in YARS,
or in its yeast ortholog TYS1, reduced yeast growth. YARS localized to
axonal termini in differentiating primary motor neuron and neuroblastoma
cultures. This specific distribution is significantly reduced in cells
expressing mutant YARS proteins. YARS was the second aminoacyl-tRNA
synthetase found to be involved in Charcot-Marie-Tooth disease, thereby
linking protein-synthesizing complexes with neurodegeneration. Dominant
mutations in GARS, which encodes glycyl-tRNA synthetase (600287), had
been found in type 2D Charcot-Marie-Tooth disease (601472) and in distal
spinal muscular atrophy type VA (DSMAVA; 600794).
*FIELD* RF
1. Jordanova, A.; Irobi, J.; Thomas, F. P.; Van Dijck, P.; Meerschaert,
K.; Dewil, M.; Dierick, I.; Jacobs, A.; De Vriendt, E.; Guergueltcheva,
V.; Rao, C. V.; Tournev, I.; and 12 others: Disrupted function
and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant
intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38: 197-202,
2006.
2. Jordanova, A.; Thomas, F. P.; Guergueltcheva, V.; Tournev, I.;
Gondim, F. A. A.; Ishpekova, B.; De Vriendt, E.; Jacobs, A.; Litvinenko,
I.; Ivanova, N.; Buzhov, B.; De Jonghe, P.; Kremensky, I.; Timmerman,
V.: Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome
1p34-p35. Am. J. Hum. Genet. 73: 1423-1430, 2003.
*FIELD* CS
INHERITANCE:
Autosomal dominant
SKELETAL:
[Feet];
Foot deformities may occur
NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Upper limb involvement may occur later;
Distal sensory impairment;
Low to normal range of nerve conduction velocity (NCV) (30-40 m/s);
Axonal regeneration on nerve biopsy;
Decreased nerve fiber density and thickness;
No onion bulb formations
MISCELLANEOUS:
Variable age of onset (7-59 years);
Begins in feet and legs (peroneal distribution);
Features intermediate between demyelinating CMT and axonal CMT;
Genetic heterogeneity (see CMTDIA 606483)
MOLECULAR BASIS:
Caused by mutation in the tyrosyl-tRNA synthetase gene (YARS, 603623.0001)
*FIELD* CN
Joanna S. Amberger - updated: 03/19/2010
*FIELD* CD
Cassandra L. Kniffin: 12/9/2003
*FIELD* ED
joanna: 03/19/2010
joanna: 1/13/2004
ckniffin: 12/11/2003
*FIELD* CN
Victor A. McKusick - updated: 2/7/2006
*FIELD* CD
Cassandra L. Kniffin: 12/5/2003
*FIELD* ED
carol: 08/01/2012
wwang: 5/11/2010
alopez: 2/10/2006
terry: 2/7/2006
alopez: 3/17/2004
carol: 12/12/2003
ckniffin: 12/8/2003