EPAS1_RAT
ID EPAS1_RAT Reviewed; 874 AA.
AC Q9JHS1;
DT 03-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 25-MAY-2022, entry version 153.
DE RecName: Full=Endothelial PAS domain-containing protein 1;
DE Short=EPAS-1;
DE AltName: Full=Hypoxia-inducible factor 2-alpha;
DE Short=HIF-2-alpha;
DE Short=HIF2-alpha;
GN Name=Epas1; Synonyms=Hif2a;
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].
RC TISSUE=Liver;
RX PubMed=11237857; DOI=10.1042/0264-6021:3540531;
RA Kietzmann T., Cornesse Y., Brechtel K., Modaressi S., Jungermann K.;
RT "Perivenous expression of the mRNA of the three hypoxia-inducible factor a-
RT subunits HIF-1a, HIF2a and HIF3a in rat liver.";
RL Biochem. J. 354:531-537(2001).
CC -!- FUNCTION: Transcription factor involved in the induction of oxygen
CC regulated genes. Heterodimerizes with ARNT; heterodimer binds to core
CC DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of
CC target gene promoters (By similarity). Regulates the vascular
CC endothelial growth factor (VEGF) expression and seems to be implicated
CC in the development of blood vessels and the tubular system of lung. May
CC also play a role in the formation of the endothelium that gives rise to
CC the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase
CC expression. Activation requires recruitment of transcriptional
CC coactivators such as CREBBP and probably EP300. Interaction with redox
CC regulatory protein APEX seems to activate CTAD (By similarity).
CC {ECO:0000250, ECO:0000250|UniProtKB:P97481}.
CC -!- SUBUNIT: Interacts with HIF3A2. Efficient DNA binding requires
CC dimerization with another bHLH protein. Heterodimerizes with ARNT;
CC heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia
CC response element (HRE) of target gene promoters. Interacts with CREBBP
CC (By similarity). Interacts with EGLN1. Interacts with VHL (By
CC similarity). {ECO:0000250|UniProtKB:P97481,
CC ECO:0000250|UniProtKB:Q99814}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P97481,
CC ECO:0000255|PROSITE-ProRule:PRU00981}. Nucleus speckle
CC {ECO:0000250|UniProtKB:P97481}. Note=Colocalizes with HIF3A in the
CC nucleus and speckles. {ECO:0000250|UniProtKB:P97481}.
CC -!- PTM: In normoxia, is probably hydroxylated on Pro-405 and Pro-530 by
CC EGLN1/PHD1, EGLN2/PHD2 and/or EGLN3/PHD3. The hydroxylated prolines
CC promote interaction with VHL, initiating rapid ubiquitination and
CC subsequent proteasomal degradation. Under hypoxia, proline
CC hydroxylation is impaired and ubiquitination is attenuated, resulting
CC in stabilization (By similarity). {ECO:0000250}.
CC -!- PTM: In normoxia, is hydroxylated on Asn-851 by HIF1AN thus probably
CC abrogating interaction with CREBBP and EP300 and preventing
CC transcriptional activation. {ECO:0000250}.
CC -!- PTM: Phosphorylated on multiple sites in the CTAD. {ECO:0000250}.
CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of
CC asparagine is (S) stereospecific within HIF CTAD domains.
CC {ECO:0000250}.
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DR EMBL; AJ277828; CAB96612.1; -; mRNA.
DR RefSeq; NP_075578.1; NM_023090.1.
DR AlphaFoldDB; Q9JHS1; -.
DR SMR; Q9JHS1; -.
DR BioGRID; 248095; 2.
DR STRING; 10116.ENSRNOP00000033874; -.
DR PaxDb; Q9JHS1; -.
DR PRIDE; Q9JHS1; -.
DR DNASU; 29452; -.
DR GeneID; 29452; -.
DR KEGG; rno:29452; -.
DR UCSC; RGD:68404; rat.
DR CTD; 2034; -.
DR RGD; 68404; Epas1.
DR eggNOG; KOG3558; Eukaryota.
DR InParanoid; Q9JHS1; -.
DR OrthoDB; 547545at2759; -.
DR PhylomeDB; Q9JHS1; -.
DR Reactome; R-RNO-1234158; Regulation of gene expression by Hypoxia-inducible Factor.
DR Reactome; R-RNO-1234174; Cellular response to hypoxia.
DR Reactome; R-RNO-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR Reactome; R-RNO-8951664; Neddylation.
DR PRO; PR:Q9JHS1; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0016607; C:nuclear speck; ISO:RGD.
DR GO; GO:0005634; C:nucleus; IDA:RGD.
DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD.
DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0050897; F:cobalt ion binding; IDA:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; ISO:RGD.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:RGD.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISO:RGD.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISO:RGD.
DR GO; GO:0001223; F:transcription coactivator binding; ISO:RGD.
DR GO; GO:0001525; P:angiogenesis; ISO:RGD.
DR GO; GO:0001974; P:blood vessel remodeling; ISO:RGD.
DR GO; GO:0030154; P:cell differentiation; ISO:RGD.
DR GO; GO:0048469; P:cell maturation; ISO:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:RGD.
DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:RGD.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0001892; P:embryonic placenta development; ISO:RGD.
DR GO; GO:0030218; P:erythrocyte differentiation; ISO:RGD.
DR GO; GO:0010467; P:gene expression; ISO:RGD.
DR GO; GO:0030097; P:hemopoiesis; ISO:RGD.
DR GO; GO:0055072; P:iron ion homeostasis; ISO:RGD.
DR GO; GO:0030324; P:lung development; ISO:RGD.
DR GO; GO:0007005; P:mitochondrion organization; ISO:RGD.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0048625; P:myoblast fate commitment; ISO:RGD.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:RGD.
DR GO; GO:0042421; P:norepinephrine biosynthetic process; IMP:RGD.
DR GO; GO:0042415; P:norepinephrine metabolic process; ISO:RGD.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:1903181; P:positive regulation of dopamine biosynthetic process; IMP:RGD.
DR GO; GO:1904655; P:positive regulation of lung alveolus development; IEP:RGD.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:RGD.
DR GO; GO:0002027; P:regulation of heart rate; ISO:RGD.
DR GO; GO:2000434; P:regulation of protein neddylation; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0043619; P:regulation of transcription from RNA polymerase II promoter in response to oxidative stress; ISO:RGD.
DR GO; GO:0001666; P:response to hypoxia; IDA:RGD.
DR GO; GO:0006979; P:response to oxidative stress; ISO:RGD.
DR GO; GO:0043129; P:surfactant homeostasis; ISO:RGD.
DR GO; GO:0007601; P:visual perception; ISO:RGD.
DR CDD; cd00130; PAS; 2.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR014887; HIF-1_TAD_C.
DR InterPro; IPR021537; HIF_alpha_subunit.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR InterPro; IPR001067; Nuc_translocat.
DR InterPro; IPR001610; PAC.
DR InterPro; IPR000014; PAS.
DR InterPro; IPR035965; PAS-like_dom_sf.
DR InterPro; IPR013655; PAS_fold_3.
DR Pfam; PF11413; HIF-1; 1.
DR Pfam; PF08778; HIF-1a_CTAD; 1.
DR Pfam; PF08447; PAS_3; 1.
DR Pfam; PF13426; PAS_9; 1.
DR PRINTS; PR00785; NCTRNSLOCATR.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; SSF47459; 1.
DR SUPFAM; SSF55785; SSF55785; 2.
DR TIGRFAMs; TIGR00229; sensory_box; 2.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
PE 2: Evidence at transcript level;
KW Activator; Angiogenesis; Developmental protein; Differentiation;
KW DNA-binding; Hydroxylation; Nucleus; Phosphoprotein; Reference proteome;
KW Repeat; Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..874
FT /note="Endothelial PAS domain-containing protein 1"
FT /id="PRO_0000127421"
FT DOMAIN 14..67
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 84..154
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 230..300
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 304..347
FT /note="PAC"
FT REGION 1..23
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 26..53
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:P97481"
FT REGION 171..192
FT /note="Required for heterodimer formation with ARNT"
FT /evidence="ECO:0000250|UniProtKB:P97481"
FT REGION 440..487
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 495..541
FT /note="NTAD"
FT REGION 624..677
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 777..824
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 834..874
FT /note="CTAD"
FT COMPBIAS 441..487
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 405
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250"
FT MOD_RES 530
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250"
FT MOD_RES 844
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P97481"
FT MOD_RES 851
FT /note="(3S)-3-hydroxyasparagine"
FT /evidence="ECO:0000250"
SQ SEQUENCE 874 AA; 96718 MW; A1FF08EB24369796 CRC64;
MTADKEKKRS SSELRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH LDKASIMRLA
ISFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA VVTQDGDMIF LSENISKFMG
LTQVELTGHS IFDFTHPCDH EEIRENLTLK TGSGFGKKNK DRSTERDFFM RMKCTVTNRG
RTVNLKSATW KVLHCTGQVR VYNNCPPHSS LCGYKEPLLS CLIIMCEPIQ HPSHMDIPLD
SKTFLSRHSM DMKFTYCDDR ILELVGYHPE ELLGRSAYEF YHALDSENMT KSHQNLCTKG
QVVSGQYRML AKHGGYVWLE TQGTVVYNPR NLQPQCIMCV NYVLSEIEKN DVVVSMDQTE
SCSSHTLMAM NSIFDTSDDV ALSEKSNYLF TNLKEEPEDL AQLAPTPGDA IISLDFGSQN
FDESSTYGKA ILPPGQPWAT ELRSHSAQSE SRSLPAFTVP QAGSPGNATP SATSSSSCST
PSSPEDYYSS LENHLKIEVI EKLFAMDTEA KDQCSTQTDF NELDLETLAP YIPMDGEDFQ
LSPICPEEPL VPESPQPNPQ HCFSTMSSIF QPLTPGASQG TFFLDKYPQQ LESRKTESEH
WPMSTIFFDA GSKGSLPPCC GQASTPLSSM GGRSNTPWPP DPPLHLGPTK WSVGNQSAEP
LGPLPLGTSQ LEPPSTPPHV SMFKMRSAKD FGARGPYMMS PAMIALSNKL KLKRQLDYEE
PAFQDTSGGD PPGTSSSHLM WKRMKSLMGG TCPLMPDKTV SASMAPDEFT QKSMRGLGQP
LRHLPPSQPP STRSPGENAK SGFPPQCYAS PFQDYSPPGA QKGSGVASRL LGPSFEPYLL
PELTRYDCEV NVPEPGSSTL LQGRDLLRAL DQAT
