ID SYNM_HUMAN Reviewed; 477 AA. AC Q96I59; G3V178; DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 27-MAR-2024, entry version 180. DE RecName: Full=Asparaginyl-tRNA synthetase {ECO:0000303|PubMed:25385316}; DE Short=AsnRS {ECO:0000303|PubMed:15779907}; DE Short=NARS2 {ECO:0000303|PubMed:25385316}; DE EC=6.1.1.22 {ECO:0000269|PubMed:25385316}; DE AltName: Full=Asparagine--tRNA ligase, mitochondrial; DE Flags: Precursor; GN Name=NARS2 {ECO:0000312|HGNC:HGNC:26274}; 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 [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [2] 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-87. 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 [4] RP IDENTIFICATION. RX PubMed=15779907; DOI=10.1021/bi047527z; RA Bonnefond L., Fender A., Rudinger-Thirion J., Giege R., Florentz C., RA Sissler M.; RT "Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: RT characterization of AspRS and TyrRS."; RL Biochemistry 44:4805-4816(2005). RN [5] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-353, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA 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 [6] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [7] RP IDENTIFICATION BY 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 [8] RP INVOLVEMENT IN COXPD24, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=25385316; DOI=10.1002/humu.22728; RA Vanlander A.V., Menten B., Smet J., De Meirleir L., Sante T., De Paepe B., RA Seneca S., Pearce S.F., Powell C.A., Vergult S., Michotte A., De Latter E., RA Vantomme L., Minczuk M., Van Coster R.; RT "Two siblings with homozygous pathogenic splice-site variant in RT mitochondrial asparaginyl-tRNA synthetase (NARS2)."; RL Hum. Mutat. 36:222-231(2015). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [10] RP INVOLVEMENT IN COXPD24, AND VARIANT COXPD24 LEU-214. RX PubMed=25629079; DOI=10.1002/mgg3.115; RA Sofou K., Kollberg G., Holmstroem M., Davila M., Darin N., Gustafsson C.M., RA Holme E., Oldfors A., Tulinius M., Asin-Cayuela J.; RT "Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the RT mitochondrial asparaginyl-tRNA synthetase and prolyl-tRNA synthetase, in RT patients with Alpers syndrome."; RL Mol. Genet. Genomic Med. 3:59-68(2015). RN [11] RP SUBCELLULAR LOCATION, SUBUNIT, INVOLVEMENT IN COXPD24, INVOLVEMENT IN RP DFNB94, VARIANTS COXPD24 323-TYR--LEU-477 DEL AND SER-381, VARIANT DFNB94 RP PHE-213, CHARACTERIZATION OF VARIANT DFNB94 PHE-213, AND CHARACTERIZATION RP OF VARIANT COXPD24 SER-381. RX PubMed=25807530; DOI=10.1371/journal.pgen.1005097; RA Simon M., Richard E.M., Wang X., Shahzad M., Huang V.H., Qaiser T.A., RA Potluri P., Mahl S.E., Davila A., Nazli S., Hancock S., Yu M., Gargus J., RA Chang R., Al-Sheqaih N., Newman W.G., Abdenur J., Starr A., Hegde R., RA Dorn T., Busch A., Park E., Wu J., Schwenzer H., Flierl A., Florentz C., RA Sissler M., Khan S.N., Li R., Guan M.X., Friedman T.B., Wu D.K., RA Procaccio V., Riazuddin S., Wallace D.C., Ahmed Z.M., Huang T., RA Riazuddin S.; RT "Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA RT synthetase, cause nonsyndromic deafness and Leigh syndrome."; RL PLoS Genet. 11:E1005097-E1005097(2015). RN [12] RP VARIANTS COXPD24 ASP-381 AND CYS-430, CHARACTERIZATION OF VARIANTS COXPD24 RP ASP-381 AND CYS-430, SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=35558980; DOI=10.21037/tp-21-570; RA Zhang Y., Zhao X., Xu Y., Chen L., Li N., Yao R., Wang X., Wang J., Yu T.; RT "Study of novel NARS2 variants in patient of combined oxidative RT phosphorylation deficiency 24."; RL Transl. Pediatr. 11:448-457(2022). CC -!- FUNCTION: Mitochondrial aminoacyl-tRNA synthetase that catalyzes the CC specific attachment of the asparagine amino acid (aa) to the homologous CC transfer RNA (tRNA), further participating in protein synthesis CC (PubMed:25385316). The reaction occurs in a two steps: asparagine is CC first activated by ATP to form Asn-AMP and then transferred to the CC acceptor end of tRNA(Asn) (Probable). {ECO:0000269|PubMed:25385316, CC ECO:0000305}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-asparagine + tRNA(Asn) = AMP + diphosphate + H(+) + L- CC asparaginyl-tRNA(Asn); Xref=Rhea:RHEA:11180, Rhea:RHEA-COMP:9659, CC Rhea:RHEA-COMP:9674, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:33019, ChEBI:CHEBI:58048, ChEBI:CHEBI:78442, CC ChEBI:CHEBI:78515, ChEBI:CHEBI:456215; EC=6.1.1.22; CC Evidence={ECO:0000269|PubMed:25385316}; CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:25807530, CC ECO:0000269|PubMed:35558980}. CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix {ECO:0000250}. Mitochondrion CC {ECO:0000269|PubMed:25807530, ECO:0000269|PubMed:35558980}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96I59-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96I59-2; Sequence=VSP_054120; CC -!- DISEASE: Combined oxidative phosphorylation deficiency 24 (COXPD24) CC [MIM:616239]: An autosomal recessive mitochondrial disorder with wide CC phenotypic variability. Some patients have a milder form affecting only CC skeletal muscle, whereas others may have a more severe disorder, CC reminiscent of Alpers syndrome. Alpers syndrome is a progressive CC neurodegenerative disorder that presents in infancy or early childhood CC and is characterized by diffuse degeneration of cerebral gray matter. CC {ECO:0000269|PubMed:25385316, ECO:0000269|PubMed:25629079, CC ECO:0000269|PubMed:25807530, ECO:0000269|PubMed:35558980}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Deafness, autosomal recessive, 94 (DFNB94) [MIM:618434]: A CC form of non-syndromic, sensorineural deafness characterized by CC prelingual, profound, bilateral hearing impairment. Sensorineural CC deafness results from damage to the neural receptors of the inner ear, CC the nerve pathways to the brain, or the area of the brain that receives CC sound information. {ECO:0000269|PubMed:25807530}. Note=The disease may CC be caused by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the class-II 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; AP003086; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP003110; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471076; EAW75061.1; -; Genomic_DNA. DR EMBL; BC007800; AAH07800.2; -; mRNA. DR CCDS; CCDS58164.1; -. [Q96I59-2] DR CCDS; CCDS8261.1; -. [Q96I59-1] DR RefSeq; NP_001230180.1; NM_001243251.1. [Q96I59-2] DR RefSeq; NP_078954.4; NM_024678.5. [Q96I59-1] DR RefSeq; XP_016873792.1; XM_017018303.1. DR AlphaFoldDB; Q96I59; -. DR SMR; Q96I59; -. DR BioGRID; 122846; 85. DR IntAct; Q96I59; 36. DR STRING; 9606.ENSP00000281038; -. DR DrugBank; DB00174; Asparagine. DR GlyGen; Q96I59; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q96I59; -. DR PhosphoSitePlus; Q96I59; -. DR SwissPalm; Q96I59; -. DR BioMuta; NARS2; -. DR DMDM; 296452944; -. DR EPD; Q96I59; -. DR jPOST; Q96I59; -. DR MassIVE; Q96I59; -. DR MaxQB; Q96I59; -. DR PaxDb; 9606-ENSP00000281038; -. DR PeptideAtlas; Q96I59; -. DR ProteomicsDB; 32283; -. DR ProteomicsDB; 76813; -. [Q96I59-1] DR Pumba; Q96I59; -. DR Antibodypedia; 17519; 225 antibodies from 26 providers. DR DNASU; 79731; -. DR Ensembl; ENST00000281038.10; ENSP00000281038.5; ENSG00000137513.11. [Q96I59-1] DR Ensembl; ENST00000528850.5; ENSP00000432635.1; ENSG00000137513.11. [Q96I59-2] DR Ensembl; ENST00000695115.1; ENSP00000511705.1; ENSG00000137513.11. [Q96I59-2] DR Ensembl; ENST00000695342.1; ENSP00000511817.1; ENSG00000137513.11. [Q96I59-2] DR Ensembl; ENST00000695343.1; ENSP00000511818.1; ENSG00000137513.11. [Q96I59-2] DR Ensembl; ENST00000695348.1; ENSP00000511823.1; ENSG00000137513.11. [Q96I59-2] DR GeneID; 79731; -. DR KEGG; hsa:79731; -. DR MANE-Select; ENST00000281038.10; ENSP00000281038.5; NM_024678.6; NP_078954.4. DR UCSC; uc001ozi.3; human. [Q96I59-1] DR AGR; HGNC:26274; -. DR CTD; 79731; -. DR DisGeNET; 79731; -. DR GeneCards; NARS2; -. DR HGNC; HGNC:26274; NARS2. DR HPA; ENSG00000137513; Low tissue specificity. DR MalaCards; NARS2; -. DR MIM; 612803; gene. DR MIM; 616239; phenotype. DR MIM; 618434; phenotype. DR neXtProt; NX_Q96I59; -. DR OpenTargets; ENSG00000137513; -. DR Orphanet; 444458; Combined oxidative phosphorylation defect type 24. DR Orphanet; 79134; DEND syndrome. DR Orphanet; 90636; Rare autosomal recessive non-syndromic sensorineural deafness type DFNB. DR PharmGKB; PA143485554; -. DR VEuPathDB; HostDB:ENSG00000137513; -. DR eggNOG; KOG0554; Eukaryota. DR GeneTree; ENSGT01030000234618; -. DR HOGENOM; CLU_004553_2_0_1; -. DR InParanoid; Q96I59; -. DR OMA; DNMDLAE; -. DR OrthoDB; 347413at2759; -. DR PhylomeDB; Q96I59; -. DR TreeFam; TF315088; -. DR BRENDA; 6.1.1.22; 2681. DR PathwayCommons; Q96I59; -. DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation. DR SignaLink; Q96I59; -. DR SIGNOR; Q96I59; -. DR BioGRID-ORCS; 79731; 262 hits in 1180 CRISPR screens. DR ChiTaRS; NARS2; human. DR GenomeRNAi; 79731; -. DR Pharos; Q96I59; Tbio. DR PRO; PR:Q96I59; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q96I59; Protein. DR Bgee; ENSG00000137513; Expressed in secondary oocyte and 201 other cell types or tissues. DR ExpressionAtlas; Q96I59; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0004816; F:asparagine-tRNA ligase activity; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0003676; F:nucleic acid binding; IEA:InterPro. DR GO; GO:0006421; P:asparaginyl-tRNA aminoacylation; ISS:UniProtKB. DR CDD; cd00776; AsxRS_core; 1. DR CDD; cd04318; EcAsnRS_like_N; 1. DR Gene3D; 2.40.50.140; Nucleic acid-binding proteins; 1. DR HAMAP; MF_00534; Asn_tRNA_synth; 1. DR InterPro; IPR004364; Aa-tRNA-synt_II. DR InterPro; IPR006195; aa-tRNA-synth_II. DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL. DR InterPro; IPR004522; Asn-tRNA-ligase. DR InterPro; IPR002312; Asp/Asn-tRNA-synth_IIb. DR InterPro; IPR012340; NA-bd_OB-fold. DR InterPro; IPR004365; NA-bd_OB_tRNA. DR NCBIfam; TIGR00457; asnS; 1. DR PANTHER; PTHR22594:SF34; ASPARAGINE--TRNA LIGASE, MITOCHONDRIAL-RELATED; 1. DR PANTHER; PTHR22594; ASPARTYL/LYSYL-TRNA SYNTHETASE; 1. DR Pfam; PF00152; tRNA-synt_2; 1. DR Pfam; PF01336; tRNA_anti-codon; 1. DR PRINTS; PR01042; TRNASYNTHASP. DR SUPFAM; SSF55681; Class II aaRS and biotin synthetases; 1. DR SUPFAM; SSF50249; Nucleic acid-binding proteins; 1. DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1. DR Genevisible; Q96I59; HS. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; Aminoacyl-tRNA synthetase; ATP-binding; KW Deafness; Disease variant; Leigh syndrome; Ligase; Mitochondrion; KW Non-syndromic deafness; Nucleotide-binding; Primary mitochondrial disease; KW Protein biosynthesis; Reference proteome; Transit peptide. FT TRANSIT 1..14 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 15..477 FT /note="Asparaginyl-tRNA synthetase" FT /id="PRO_0000250722" FT MOD_RES 353 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT VAR_SEQ 1..227 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_054120" FT VARIANT 87 FT /note="N -> T (in dbSNP:rs10501429)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_052636" FT VARIANT 213 FT /note="V -> F (in DFNB94; probable loss-of-function FT variant; unable to rescue mitochondrial respiratory chain FT defects in NARS2 null fibroblasts; does not affect FT homodimerization; does not affect localization to FT mitochondrion; dbSNP:rs756725793)" FT /evidence="ECO:0000269|PubMed:25807530" FT /id="VAR_073723" FT VARIANT 214 FT /note="P -> L (in COXPD24; dbSNP:rs730882155)" FT /evidence="ECO:0000269|PubMed:25629079" FT /id="VAR_073250" FT VARIANT 323..477 FT /note="Missing (in COXPD24)" FT /evidence="ECO:0000269|PubMed:25807530" FT /id="VAR_082311" FT VARIANT 381 FT /note="N -> D (in COXPD24; uncertain significance; no FT effect on homodimer formation; does not affect localization FT to mitochondrion)" FT /evidence="ECO:0000269|PubMed:35558980" FT /id="VAR_086708" FT VARIANT 381 FT /note="N -> S (in COXPD24; does not form homodimers; does FT not affect localization to mitochondrion; FT dbSNP:rs1565216037)" FT /evidence="ECO:0000269|PubMed:25807530" FT /id="VAR_073724" FT VARIANT 430 FT /note="W -> C (in COXPD24; uncertain significance; no FT effect on homodimer formation; does not affect localization FT to mitochondrion)" FT /evidence="ECO:0000269|PubMed:35558980" FT /id="VAR_086709" SQ SEQUENCE 477 AA; 54090 MW; 1F4C78E0B6F5500C CRC64; MLGVRCLLRS VRFCSSAPFP KHKPSAKLSV RDALGAQNAS GERIKIQGWI RSVRSQKEVL FLHVNDGSSL ESLQVVADSG LDSRELNFGS SVEVQGQLIK SPSKRQNVEL KAEKIKVIGN CDAKDFPIKY KERHPLEYLR QYPHFRCRTN VLGSILRIRS EATAAIHSFF KDSGFVHIHT PIITSNDSEG AGELFQLEPS GKLKVPEENF FNVPAFLTVS GQLHLEVMSG AFTQVFTFGP TFRAENSQSR RHLAEFYMIE AEISFVDSLQ DLMQVIEELF KATTMMVLSK CPEDVELCHK FIAPGQKDRL EHMLKNNFLI ISYTEAVEIL KQASQNFTFT PEWGADLRTE HEKYLVKHCG NIPVFVINYP LTLKPFYMRD NEDGPQHTVA AVDLLVPGVG ELFGGGLREE RYHFLEERLA RSGLTEVYQW YLDLRRFGSV PHGGFGMGFE RYLQCILGVD NIKDVIPFPR FPHSCLL //