DYR1A_RAT
ID DYR1A_RAT Reviewed; 763 AA.
AC Q63470;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 2.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=Dual specificity tyrosine-phosphorylation-regulated kinase 1A;
DE EC=2.7.12.1 {ECO:0000269|PubMed:22998443};
DE AltName: Full=Dual specificity YAK1-related kinase;
DE AltName: Full=Protein kinase minibrain homolog;
DE Short=MNBH;
DE AltName: Full=RP86;
GN Name=Dyrk1a; Synonyms=Dyrk;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), FUNCTION, TISSUE SPECIFICITY,
RP PHOSPHORYLATION AT TYR-219; TYR-319 AND TYR-321, AND MUTAGENESIS OF
RP LYS-188; TYR-219; TYR-319 AND TYR-321.
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=8631952; DOI=10.1074/jbc.271.7.3488;
RA Kentrup H., Becker W., Heukelbach J., Wilmes A., Schuermann A.,
RA Huppertz C., Kainulainen H., Joost H.-G.;
RT "Dyrk, a dual specificity protein kinase with unique structural features
RT whose activity is dependent on tyrosine residues between subdomains VII and
RT VIII.";
RL J. Biol. Chem. 271:3488-3495(1996).
RN [2]
RP SEQUENCE REVISION.
RA Kentrup H.;
RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=9748265; DOI=10.1074/jbc.273.40.25893;
RA Becker W., Weber Y., Wetzel K., Eirmbter K., Tejedor F.J., Joost H.-G.;
RT "Sequence characteristics, subcellular localization, and substrate
RT specificity of DYRK-related kinases, a novel family of dual specificity
RT protein kinases.";
RL J. Biol. Chem. 273:25893-25902(1998).
RN [4]
RP FUNCTION, AND INTERACTION WITH SEPTIN4 AND SEPTIN5.
RX PubMed=18938227; DOI=10.1016/j.neuroscience.2008.09.034;
RA Sitz J.H., Baumgaertel K., Haemmerle B., Papadopoulos C., Hekerman P.,
RA Tejedor F.J., Becker W., Lutz B.;
RT "The Down syndrome candidate dual-specificity tyrosine phosphorylation-
RT regulated kinase 1A phosphorylates the neurodegeneration-related septin
RT 4.";
RL Neuroscience 157:596-605(2008).
RN [5]
RP SUBCELLULAR LOCATION, INTERACTION WITH SRSF6, FUNCTION, MUTAGENESIS OF
RP LYS-188, AND TISSUE SPECIFICITY.
RX PubMed=22767602; DOI=10.1074/jbc.m112.355412;
RA Yin X., Jin N., Gu J., Shi J., Zhou J., Gong C.X., Iqbal K.,
RA Grundke-Iqbal I., Liu F.;
RT "Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)
RT modulates serine/arginine-rich protein 55 (SRp55)-promoted Tau exon 10
RT inclusion.";
RL J. Biol. Chem. 287:30497-30506(2012).
RN [6]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND TISSUE SPECIFICITY.
RX PubMed=22998443; DOI=10.1021/jm301034u;
RA Tahtouh T., Elkins J.M., Filippakopoulos P., Soundararajan M., Burgy G.,
RA Durieu E., Cochet C., Schmid R.S., Lo D.C., Delhommel F., Oberholzer A.E.,
RA Pearl L.H., Carreaux F., Bazureau J.P., Knapp S., Meijer L.;
RT "Selectivity, cocrystal structures, and neuroprotective properties of
RT leucettines, a family of protein kinase inhibitors derived from the marine
RT sponge alkaloid leucettamine B.";
RL J. Med. Chem. 55:9312-9330(2012).
CC -!- FUNCTION: Dual-specificity kinase which possesses both serine/threonine
CC and tyrosine kinase activities (PubMed:18938227). Plays an important
CC role in double-strand breaks (DSBs) repair following DNA damage.
CC Mechanistically, phosphorylates RNF169 and increases its ability to
CC block accumulation of TP53BP1 at the DSB sites thereby promoting
CC homologous recombination repair (HRR) (By similarity). May play a role
CC in a signaling pathway regulating nuclear functions of cell
CC proliferation. Modulates alternative splicing by phosphorylating the
CC splice factor SRSF6 (By similarity). Exhibits a substrate preference
CC for proline at position P+1 and arginine at position P-3. Has pro-
CC survival function and negatively regulates the apoptotic process.
CC Promotes cell survival upon genotoxic stress through phosphorylation of
CC SIRT1. This in turn inhibits TP53 activity and apoptosis (By
CC similarity). Phosphorylates SEPTIN4, SEPTIN5 and SF3B1 at 'Thr-434'
CC (PubMed:18938227). {ECO:0000250|UniProtKB:Q61214,
CC ECO:0000250|UniProtKB:Q9NR20, ECO:0000269|PubMed:18938227,
CC ECO:0000269|PubMed:22767602, ECO:0000269|PubMed:8631952,
CC ECO:0000269|PubMed:9748265}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.12.1;
CC Evidence={ECO:0000269|PubMed:22998443};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.12.1; Evidence={ECO:0000269|PubMed:22998443};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.12.1;
CC Evidence={ECO:0000269|PubMed:22998443};
CC -!- ACTIVITY REGULATION: Inhibited by RANBP9 (By similarity). Inhibited by
CC harmine, leucettamine B and leucettine L41 (PubMed:22998443).
CC {ECO:0000250|UniProtKB:Q13627, ECO:0000269|PubMed:22998443}.
CC -!- SUBUNIT: Interacts with RANBP9. Interacts with RAD54L2/ARIP4. Interacts
CC with CRY2 (By similarity). Interacts with WDR68 (By similarity).
CC Interacts with SRSF6 (PubMed:22767602). Interacts with SIRT1 (By
CC similarity). Interacts with SEPTIN4 and SEPTIN5 (PubMed:18938227).
CC {ECO:0000250|UniProtKB:Q13627, ECO:0000250|UniProtKB:Q61214,
CC ECO:0000269|PubMed:18938227, ECO:0000269|PubMed:22767602}.
CC -!- SUBCELLULAR LOCATION: Nucleus speckle {ECO:0000269|PubMed:22767602,
CC ECO:0000269|PubMed:9748265}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Long;
CC IsoId=Q63470-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=Q63470-2; Sequence=VSP_004924;
CC -!- TISSUE SPECIFICITY: Detected in brain (at protein level). Ubiquitous.
CC {ECO:0000269|PubMed:22767602, ECO:0000269|PubMed:22998443,
CC ECO:0000269|PubMed:8631952, ECO:0000269|PubMed:9748265}.
CC -!- DOMAIN: The polyhistidine repeats act as targeting signals to nuclear
CC speckles. {ECO:0000250}.
CC -!- PTM: Can also autophosphorylate on serine and threonine residues (in
CC vitro) (By similarity). Autophosphorylated on numerous tyrosine
CC residues (PubMed:8631952). {ECO:0000250|UniProtKB:Q13627,
CC ECO:0000269|PubMed:8631952}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MNB/DYRK subfamily. {ECO:0000305}.
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DR EMBL; X79769; CAA56164.1; -; mRNA.
DR RefSeq; NP_036923.1; NM_012791.3. [Q63470-1]
DR RefSeq; XP_006248093.1; XM_006248031.3. [Q63470-1]
DR RefSeq; XP_008766785.1; XM_008768563.2. [Q63470-1]
DR RefSeq; XP_008766786.1; XM_008768564.1. [Q63470-1]
DR RefSeq; XP_008766787.1; XM_008768565.2. [Q63470-2]
DR AlphaFoldDB; Q63470; -.
DR SMR; Q63470; -.
DR BioGRID; 247295; 6.
DR ELM; Q63470; -.
DR IntAct; Q63470; 5.
DR MINT; Q63470; -.
DR STRING; 10116.ENSRNOP00000042446; -.
DR BindingDB; Q63470; -.
DR ChEMBL; CHEMBL5508; -.
DR DrugCentral; Q63470; -.
DR GuidetoPHARMACOLOGY; 2009; -.
DR iPTMnet; Q63470; -.
DR PhosphoSitePlus; Q63470; -.
DR PaxDb; Q63470; -.
DR PRIDE; Q63470; -.
DR Ensembl; ENSRNOT00000050342; ENSRNOP00000042446; ENSRNOG00000001662. [Q63470-1]
DR Ensembl; ENSRNOT00000114109; ENSRNOP00000096172; ENSRNOG00000001662. [Q63470-2]
DR GeneID; 25255; -.
DR KEGG; rno:25255; -.
DR UCSC; RGD:2528; rat. [Q63470-1]
DR CTD; 1859; -.
DR RGD; 2528; Dyrk1a.
DR eggNOG; KOG0667; Eukaryota.
DR GeneTree; ENSGT00940000157408; -.
DR HOGENOM; CLU_000288_5_6_1; -.
DR InParanoid; Q63470; -.
DR OMA; PPIGWTA; -.
DR OrthoDB; 689446at2759; -.
DR PhylomeDB; Q63470; -.
DR TreeFam; TF314624; -.
DR BRENDA; 2.7.12.1; 5301.
DR Reactome; R-RNO-1538133; G0 and Early G1.
DR PRO; PR:Q63470; -.
DR Proteomes; UP000002494; Chromosome 11.
DR Bgee; ENSRNOG00000001662; Expressed in skeletal muscle tissue and 19 other tissues.
DR Genevisible; Q63470; RN.
DR GO; GO:0030424; C:axon; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; ISO:RGD.
DR GO; GO:0030425; C:dendrite; ISO:RGD.
DR GO; GO:0016607; C:nuclear speck; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:1990904; C:ribonucleoprotein complex; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; ISO:RGD.
DR GO; GO:0004672; F:protein kinase activity; IDA:RGD.
DR GO; GO:0043621; F:protein self-association; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0004712; F:protein serine/threonine/tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0048156; F:tau protein binding; ISO:RGD.
DR GO; GO:0003713; F:transcription coactivator activity; IBA:GO_Central.
DR GO; GO:0034205; P:amyloid-beta formation; ISO:RGD.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0043518; P:negative regulation of DNA damage response, signal transduction by p53 class mediator; ISO:RGD.
DR GO; GO:0031115; P:negative regulation of microtubule polymerization; ISO:RGD.
DR GO; GO:0048025; P:negative regulation of mRNA splicing, via spliceosome; ISO:RGD.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:UniProtKB.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IGI:ARUK-UCL.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISO:RGD.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0090312; P:positive regulation of protein deacetylation; ISO:RGD.
DR GO; GO:0033120; P:positive regulation of RNA splicing; IMP:ARUK-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IBA:GO_Central.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; IDA:UniProtKB.
DR CDD; cd14226; PKc_DYRK1; 1.
DR InterPro; IPR028318; DYRK1A/B_MNB.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR044131; PKc_DYR1A/1B.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR PANTHER; PTHR24058:SF121; PTHR24058:SF121; 1.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; Kinase; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase; Tyrosine-protein kinase.
FT CHAIN 1..763
FT /note="Dual specificity tyrosine-phosphorylation-regulated
FT kinase 1A"
FT /id="PRO_0000085933"
FT DOMAIN 159..479
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 33..56
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 115..136
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 408..442
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 485..540
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 596..679
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 744..763
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 117..134
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 34..56
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 485..528
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 601..624
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 627..679
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 287
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 165..173
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 188
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 238..241
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 14
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 111
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 140
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 145
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 159
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 177
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 219
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:8631952"
FT MOD_RES 310
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 319
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:8631952"
FT MOD_RES 321
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:8631952"
FT MOD_RES 402
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 449
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 529
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 538
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q61214"
FT MOD_RES 748
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT MOD_RES 758
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q13627"
FT VAR_SEQ 70..78
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000305"
FT /id="VSP_004924"
FT MUTAGEN 188
FT /note="K->R: Abolishes autophosphorylation. Retains
FT marginal kinase activity towards histones."
FT /evidence="ECO:0000269|PubMed:22767602,
FT ECO:0000269|PubMed:8631952"
FT MUTAGEN 219
FT /note="Y->F: Reduced autophosphorylation on tyrosine, but
FT retains some kinase activity towards histones."
FT /evidence="ECO:0000269|PubMed:8631952"
FT MUTAGEN 319
FT /note="Y->F: Suppressed autophosphorylation on tyrosine and
FT reduced tyrosine, threonine and serine kinase activity
FT towards histones; when associated with F-321."
FT /evidence="ECO:0000269|PubMed:8631952"
FT MUTAGEN 321
FT /note="Y->F: Suppressed autophosphorylation on tyrosine and
FT reduced tyrosine, threonine and serine kinase activity
FT towards histones; when associated with F-319."
FT /evidence="ECO:0000269|PubMed:8631952"
SQ SEQUENCE 763 AA; 85541 MW; CB5EC7EC4C1F9A47 CRC64;
MHTGGETSAC KPSSVRLAPS FSFHAAGLQM AAQMPHSHQY SDRRQPNISD QQVSALSYSD
QIQQPLTNQV MPDIVMLQRR MPQTFRDPAT APLRKLSVDL IKTYKHINEV YYAKKKRRHQ
QGQGDDSSHK KERKVYNDGY DDDNYDYIVK NGEKWMDRYE IDSLIGKGSF GQVVKAYDRV
EQEWVAIKII KNKKAFLNQA QIEVRLLELM NKHDTEMKYY IVHLKRHFMF RNHLCLVFEM
LSYNLYDLLR NTNFRGVSLN LTRKFAQQMC TALLFLATPE LSIIHCDLKP ENILLCNPKR
SAIKIVDFGS SCQLGQRIYQ YIQSRFYRSP EVLLGMPYDL AIDMWSLGCI LVEMHTGEPL
FSGANEVDQM NKIVEVLGIP PAHILDQAPK ARKFFEKLPD GTWSLKKTKD GKREYKPPGT
RKLHNILGVE TGGPGGRRAG ESGHTVADYL KFKDLILRML DYDPKTRIQP YYALQHSFFK
KTADEGTNTS NSVSTSPAME QSQSSGTTSS TSSSSGGSSG TSNSGRARSD PTHQHRHSGG
HFAAAVQAMD CETHSPQVRQ QFPAPLGWSG TEAPTQVTVE THPVQETTFH VAPQQNALHH
HHGNSSHHHH HHHHHHHHHG QQALGNRTRP RVYNSPTNSS STQDSMEVGH SHHSMTSLSS
STTSSSTSSS STGNQGNQAY QNRPVAANTL DFGQNGAMDV NLTVYSNPRQ ETGIAGHPTY
QFSANTGPAH YMTEGHLTMR QGADREESPM TGVCVQQSPV ASS
