SYDM_HUMAN
ID SYDM_HUMAN Reviewed; 645 AA.
AC Q6PI48;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 172.
DE RecName: Full=Aspartate--tRNA ligase, mitochondrial;
DE EC=6.1.1.12 {ECO:0000269|PubMed:15779907, ECO:0000269|PubMed:23275545};
DE AltName: Full=Aspartyl-tRNA synthetase;
DE Short=AspRS;
DE Flags: Precursor;
GN Name=DARS2;
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=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [3]
RP SUBCELLULAR LOCATION, SUBUNIT, AND CATALYTIC ACTIVITY.
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 [4]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-382, 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 [5]
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 [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-242, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (3.70 ANGSTROMS) OF 41-645, SUBUNIT, AND CATALYTIC
RP ACTIVITY.
RX PubMed=23275545; DOI=10.1093/nar/gks1322;
RA Neuenfeldt A., Lorber B., Ennifar E., Gaudry A., Sauter C., Sissler M.,
RA Florentz C.;
RT "Thermodynamic properties distinguish human mitochondrial aspartyl-tRNA
RT synthetase from bacterial homolog with same 3D architecture.";
RL Nucleic Acids Res. 41:2698-2708(2013).
RN [10]
RP VARIANTS LBSL GLY-45; PHE-152; HIS-179; LYS-184; LYS-248; GLN-263; VAL-560;
RP PHE-613; VAL-626; GLN-626 AND CYS-629.
RX PubMed=17384640; DOI=10.1038/ng2013;
RA Scheper G.C., van der Klok T., van Andel R.J., van Berkel C.G.M.,
RA Sissler M., Smet J., Muravina T.I., Serkov S.V., Uziel G., Bugiani M.,
RA Schiffmann R., Kraegeloh-Mann I., Smeitink J.A.M., Florentz C.,
RA Van Coster R., Pronk J.C., van der Knaap M.S.;
RT "Mitochondrial aspartyl-tRNA synthetase deficiency causes
RT leukoencephalopathy with brain stem and spinal cord involvement and lactate
RT elevation.";
RL Nat. Genet. 39:534-539(2007).
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-aspartate + tRNA(Asp) = AMP + diphosphate + L-
CC aspartyl-tRNA(Asp); Xref=Rhea:RHEA:19649, Rhea:RHEA-COMP:9660,
CC Rhea:RHEA-COMP:9678, ChEBI:CHEBI:29991, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:78442, ChEBI:CHEBI:78516,
CC ChEBI:CHEBI:456215; EC=6.1.1.12;
CC Evidence={ECO:0000269|PubMed:15779907, ECO:0000269|PubMed:23275545};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:15779907,
CC ECO:0000269|PubMed:23275545}.
CC -!- INTERACTION:
CC Q6PI48; P54886: ALDH18A1; NbExp=3; IntAct=EBI-3917045, EBI-1210304;
CC Q6PI48; Q16853: AOC3; NbExp=3; IntAct=EBI-3917045, EBI-3921628;
CC Q6PI48; O14735: CDIPT; NbExp=3; IntAct=EBI-3917045, EBI-358858;
CC Q6PI48; Q4VAQ0: COL8A2; NbExp=3; IntAct=EBI-3917045, EBI-10241815;
CC Q6PI48; P49447: CYB561; NbExp=3; IntAct=EBI-3917045, EBI-8646596;
CC Q6PI48; Q9UGM5: FETUB; NbExp=3; IntAct=EBI-3917045, EBI-13049494;
CC Q6PI48; P10809: HSPD1; NbExp=3; IntAct=EBI-3917045, EBI-352528;
CC Q6PI48; Q04941: PLP2; NbExp=3; IntAct=EBI-3917045, EBI-608347;
CC Q6PI48; C9JKN6: THSD7B; NbExp=3; IntAct=EBI-3917045, EBI-17192156;
CC Q6PI48; Q8WW34-2: TMEM239; NbExp=3; IntAct=EBI-3917045, EBI-11528917;
CC Q6PI48; Q86UF1: TSPAN33; NbExp=3; IntAct=EBI-3917045, EBI-12045841;
CC Q6PI48; Q53HI1: UNC50; NbExp=3; IntAct=EBI-3917045, EBI-7601760;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:15779907}.
CC -!- DISEASE: Leukoencephalopathy with brainstem and spinal cord involvement
CC and lactate elevation (LBSL) [MIM:611105]: Autosomal recessive disease
CC and is defined on the basis of a highly characteristic constellation of
CC abnormalities observed by magnetic resonance imaging and spectroscopy.
CC Affected individuals develop slowly progressive cerebellar ataxia,
CC spasticity, and dorsal column dysfunction, sometimes with a mild
CC cognitive deficit or decline. {ECO:0000269|PubMed:17384640}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase family.
CC Type 1 subfamily. {ECO:0000305}.
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DR EMBL; AL109921; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC045173; AAH45173.1; -; mRNA.
DR CCDS; CCDS1311.1; -.
DR RefSeq; NP_060592.2; NM_018122.4.
DR PDB; 4AH6; X-ray; 3.70 A; A/B/C/D=41-645.
DR PDBsum; 4AH6; -.
DR AlphaFoldDB; Q6PI48; -.
DR SMR; Q6PI48; -.
DR BioGRID; 120459; 138.
DR IntAct; Q6PI48; 37.
DR MINT; Q6PI48; -.
DR STRING; 9606.ENSP00000355086; -.
DR DrugBank; DB00128; Aspartic acid.
DR iPTMnet; Q6PI48; -.
DR PhosphoSitePlus; Q6PI48; -.
DR SwissPalm; Q6PI48; -.
DR BioMuta; DARS2; -.
DR DMDM; 74758347; -.
DR EPD; Q6PI48; -.
DR jPOST; Q6PI48; -.
DR MassIVE; Q6PI48; -.
DR MaxQB; Q6PI48; -.
DR PaxDb; Q6PI48; -.
DR PeptideAtlas; Q6PI48; -.
DR PRIDE; Q6PI48; -.
DR ProteomicsDB; 67139; -.
DR Antibodypedia; 20564; 185 antibodies from 24 providers.
DR DNASU; 55157; -.
DR Ensembl; ENST00000649689.2; ENSP00000497569.1; ENSG00000117593.12.
DR GeneID; 55157; -.
DR KEGG; hsa:55157; -.
DR MANE-Select; ENST00000649689.2; ENSP00000497569.1; NM_018122.5; NP_060592.2.
DR UCSC; uc001gjh.3; human.
DR CTD; 55157; -.
DR DisGeNET; 55157; -.
DR GeneCards; DARS2; -.
DR GeneReviews; DARS2; -.
DR HGNC; HGNC:25538; DARS2.
DR HPA; ENSG00000117593; Low tissue specificity.
DR MalaCards; DARS2; -.
DR MIM; 610956; gene.
DR MIM; 611105; phenotype.
DR neXtProt; NX_Q6PI48; -.
DR OpenTargets; ENSG00000117593; -.
DR Orphanet; 137898; Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome.
DR PharmGKB; PA142672015; -.
DR VEuPathDB; HostDB:ENSG00000117593; -.
DR eggNOG; KOG2411; Eukaryota.
DR GeneTree; ENSGT01030000234618; -.
DR HOGENOM; CLU_014330_3_1_1; -.
DR InParanoid; Q6PI48; -.
DR OMA; YQLDVEM; -.
DR OrthoDB; 697974at2759; -.
DR PhylomeDB; Q6PI48; -.
DR TreeFam; TF314827; -.
DR BRENDA; 6.1.1.12; 2681.
DR PathwayCommons; Q6PI48; -.
DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation.
DR SignaLink; Q6PI48; -.
DR BioGRID-ORCS; 55157; 211 hits in 1086 CRISPR screens.
DR ChiTaRS; DARS2; human.
DR GenomeRNAi; 55157; -.
DR Pharos; Q6PI48; Tbio.
DR PRO; PR:Q6PI48; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q6PI48; protein.
DR Bgee; ENSG00000117593; Expressed in rectum and 111 other tissues.
DR ExpressionAtlas; Q6PI48; baseline and differential.
DR Genevisible; Q6PI48; HS.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0004815; F:aspartate-tRNA ligase activity; IDA:UniProtKB.
DR GO; GO:0050560; F:aspartate-tRNA(Asn) ligase activity; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; TAS:BHF-UCL.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0000049; F:tRNA binding; TAS:BHF-UCL.
DR GO; GO:0006422; P:aspartyl-tRNA aminoacylation; IBA:GO_Central.
DR GO; GO:0070145; P:mitochondrial asparaginyl-tRNA aminoacylation; IDA:UniProtKB.
DR GO; GO:0043039; P:tRNA aminoacylation; IDA:BHF-UCL.
DR Gene3D; 2.40.50.140; -; 1.
DR Gene3D; 3.30.1360.30; -; 1.
DR Gene3D; 3.30.930.10; -; 1.
DR HAMAP; MF_00044; Asp_tRNA_synth_type1; 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; IPR004524; Asp-tRNA-ligase_1.
DR InterPro; IPR002312; Asp/Asn-tRNA-synth_IIb.
DR InterPro; IPR004115; GAD-like_sf.
DR InterPro; IPR029351; GAD_dom.
DR InterPro; IPR012340; NA-bd_OB-fold.
DR InterPro; IPR004365; NA-bd_OB_tRNA.
DR PANTHER; PTHR22594:SF5; PTHR22594:SF5; 1.
DR Pfam; PF02938; GAD; 1.
DR Pfam; PF00152; tRNA-synt_2; 1.
DR Pfam; PF01336; tRNA_anti-codon; 1.
DR PRINTS; PR01042; TRNASYNTHASP.
DR SUPFAM; SSF50249; SSF50249; 1.
DR SUPFAM; SSF55261; SSF55261; 1.
DR SUPFAM; SSF55681; SSF55681; 1.
DR TIGRFAMs; TIGR00459; aspS_bact; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Disease variant; Ligase; Mitochondrion; Nucleotide-binding; Phosphoprotein;
KW Protein biosynthesis; Reference proteome; Transit peptide.
FT TRANSIT 1..47
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 48..645
FT /note="Aspartate--tRNA ligase, mitochondrial"
FT /id="PRO_0000250736"
FT REGION 244..247
FT /note="Aspartate"
FT /evidence="ECO:0000250"
FT BINDING 266..268
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 266
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250"
FT BINDING 535
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT BINDING 542
FT /ligand="L-aspartate"
FT /ligand_id="ChEBI:CHEBI:29991"
FT /evidence="ECO:0000250"
FT BINDING 584..587
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 219
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q3KRD0"
FT MOD_RES 242
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 382
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VARIANT 10
FT /note="L -> V (in dbSNP:rs4427454)"
FT /id="VAR_027612"
FT VARIANT 45
FT /note="S -> G (in LBSL; dbSNP:rs121918209)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037015"
FT VARIANT 152
FT /note="C -> F (in LBSL; dbSNP:rs121918208)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037016"
FT VARIANT 179
FT /note="R -> H (in LBSL; dbSNP:rs121918210)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037017"
FT VARIANT 184
FT /note="Q -> K (in LBSL; dbSNP:rs1469160736)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037018"
FT VARIANT 196
FT /note="K -> R (in dbSNP:rs35515638)"
FT /id="VAR_034525"
FT VARIANT 248
FT /note="Q -> K (in LBSL; dbSNP:rs772489337)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037019"
FT VARIANT 263
FT /note="R -> Q (in LBSL; dbSNP:rs121918207)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037020"
FT VARIANT 560
FT /note="D -> V (in LBSL; dbSNP:rs770525873)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037021"
FT VARIANT 613
FT /note="L -> F (in LBSL; dbSNP:rs121918212)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037022"
FT VARIANT 626
FT /note="L -> Q (in LBSL; dbSNP:rs121918213)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037023"
FT VARIANT 626
FT /note="L -> V (in LBSL; dbSNP:rs121918205)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037024"
FT VARIANT 629
FT /note="Y -> C (in LBSL; dbSNP:rs761675657)"
FT /evidence="ECO:0000269|PubMed:17384640"
FT /id="VAR_037025"
SQ SEQUENCE 645 AA; 73563 MW; 8B668751542F01A1 CRC64;
MYFPSWLSQL YRGLSRPIRR TTQPIWGSLY RSLLQSSQRR IPEFSSFVVR TNTCGELRSS
HLGQEVTLCG WIQYRRQNTF LVLRDFDGLV QVIIPQDESA ASVKKILCEA PVESVVQVSG
TVISRPAGQE NPKMPTGEIE IKVKTAELLN ACKKLPFEIK NFVKKTEALR LQYRYLDLRS
FQMQYNLRLR SQMVMKMREY LCNLHGFVDI ETPTLFKRTP GGAKEFLVPS REPGKFYSLP
QSPQQFKQLL MVGGLDRYFQ VARCYRDEGS RPDRQPEFTQ IDIEMSFVDQ TGIQSLIEGL
LQYSWPNDKD PVVVPFPTMT FAEVLATYGT DKPDTRFGMK IIDISDVFRN TEIGFLQDAL
SKPHGTVKAI CIPEGAKYLK RKDIESIRNF AADHFNQEIL PVFLNANRNW NSPVANFIME
SQRLELIRLM ETQEEDVVLL TAGEHNKACS LLGKLRLECA DLLETRGVVL RDPTLFSFLW
VVDFPLFLPK EENPRELESA HHPFTAPHPS DIHLLYTEPK KARSQHYDLV LNGNEIGGGS
IRIHNAELQR YILATLLKED VKMLSHLLQA LDYGAPPHGG IALGLDRLIC LVTGSPSIRD
VIAFPKSFRG HDLMSNTPDS VPPEELKPYH IRVSKPTDSK AERAH
