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P97481

- EPAS1_MOUSE

UniProt

P97481 - EPAS1_MOUSE

Protein

Endothelial PAS domain-containing protein 1

Gene

Epas1

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 139 (01 Oct 2014)
      Sequence version 2 (15 Dec 1998)
      Previous versions | rss
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    Functioni

    Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD By similarity.By similarity

    GO - Molecular functioni

    1. DNA binding Source: MGI
    2. histone acetyltransferase binding Source: UniProtKB
    3. protein heterodimerization activity Source: MGI
    4. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: MGI
    5. sequence-specific DNA binding Source: Ensembl
    6. sequence-specific DNA binding transcription factor activity Source: MGI
    7. signal transducer activity Source: InterPro
    8. transcription factor binding Source: MGI

    GO - Biological processi

    1. angiogenesis Source: MGI
    2. blood vessel remodeling Source: MGI
    3. cell differentiation Source: MGI
    4. cell maturation Source: MGI
    5. cellular response to hypoxia Source: UniProtKB
    6. embryonic placenta development Source: MGI
    7. erythrocyte differentiation Source: MGI
    8. hemopoiesis Source: MGI
    9. lung development Source: MGI
    10. mitochondrion organization Source: MGI
    11. myoblast fate commitment Source: BHF-UCL
    12. norepinephrine metabolic process Source: MGI
    13. positive regulation of transcription from RNA polymerase II promoter Source: MGI
    14. regulation of heart rate Source: MGI
    15. regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: MGI
    16. response to hypoxia Source: MGI
    17. response to oxidative stress Source: MGI
    18. surfactant homeostasis Source: MGI
    19. visual perception Source: MGI

    Keywords - Molecular functioni

    Activator, Developmental protein

    Keywords - Biological processi

    Angiogenesis, Differentiation, Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_199104. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_199107. Regulation of gene expression by Hypoxia-inducible Factor.
    REACT_199108. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_216222. Transcriptional regulation of pluripotent stem cells.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Endothelial PAS domain-containing protein 1
    Short name:
    EPAS-1
    Alternative name(s):
    HIF-1-alpha-like factor
    Short name:
    HLF
    Short name:
    mHLF
    HIF-related factor
    Short name:
    HRF
    Hypoxia-inducible factor 2-alpha
    Short name:
    HIF-2-alpha
    Short name:
    HIF2-alpha
    Gene namesi
    Name:Epas1
    Synonyms:Hif2a
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 17

    Organism-specific databases

    MGIiMGI:109169. Epas1.

    Subcellular locationi

    Nucleus PROSITE-ProRule annotation

    GO - Cellular componenti

    1. cytoplasm Source: MGI
    2. nucleus Source: MGI
    3. transcription factor complex Source: MGI

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi530 – 5301P → A: Confers transcriptional activity at normoxia; when associated with A-851. 1 Publication
    Mutagenesisi844 – 8441T → A: Decreases interaction with CREBBP. 1 Publication
    Mutagenesisi851 – 8511N → A: Confers transcriptional activity at normoxia; when associated with A-530. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 874874Endothelial PAS domain-containing protein 1PRO_0000127420Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei405 – 40514-hydroxyprolineBy similarity
    Modified residuei530 – 53014-hydroxyprolineBy similarity
    Modified residuei844 – 8441Phosphothreonine1 Publication
    Modified residuei851 – 8511(3S)-3-hydroxyasparagine1 Publication

    Post-translational modificationi

    In normoxia, is probably hydroxylated on Pro-405 and Pro-530 by EGLN1/PHD1, EGLN2/PHD2 and/or EGLN3/PHD3. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization By similarity.By similarity
    In normoxia, is hydroxylated on Asn-851 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.1 Publication
    Phosphorylated on multiple sites in the CTAD.1 Publication
    The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.1 Publication

    Keywords - PTMi

    Hydroxylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiP97481.
    PRIDEiP97481.

    PTM databases

    PhosphoSiteiP97481.

    Expressioni

    Tissue specificityi

    Expressed in most tissues, with highest levels in lung, followed by heart, kidney, brain and liver. Predominantly expressed in endothelial cells. Also found in smooth muscle cells of the uterus, neurons, and brown adipose tissue. High expression in embryonic choroid plexus and kidney glomeruli.

    Developmental stagei

    In day 11 embryo, expression is almost exclusively seen in endothelial cells of the intersegmental blood vessels separating the somites, the atrial and ventricular chambers of the heart, and the dorsal aorta. High expression also occurs in extraembryonic membranes. In the developing brain of day 13 embryo, endothelial cells of the highly vascularized choroid plexus contain high levels of EPAS1.

    Gene expression databases

    BgeeiP97481.
    CleanExiMM_EPAS1.
    GenevestigatoriP97481.

    Interactioni

    Subunit structurei

    Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT. Interacts with CREBPB.1 Publication

    Protein-protein interaction databases

    BioGridi199458. 3 interactions.
    DIPiDIP-46109N.
    STRINGi10090.ENSMUSP00000107892.

    Structurei

    3D structure databases

    ProteinModelPortaliP97481.
    SMRiP97481. Positions 16-348, 840-872.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini14 – 6754bHLHPROSITE-ProRule annotationAdd
    BLAST
    Domaini84 – 15471PAS 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini230 – 30071PAS 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini304 – 34744PACAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni495 – 54147NTADAdd
    BLAST
    Regioni834 – 87441CTADAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi471 – 4799Poly-Ser

    Sequence similaritiesi

    Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
    Contains 2 PAS (PER-ARNT-SIM) domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiNOG289264.
    GeneTreeiENSGT00730000110711.
    HOGENOMiHOG000234306.
    HOVERGENiHBG060456.
    InParanoidiP97481.
    KOiK09095.
    OMAiDPPLHFG.
    OrthoDBiEOG7JDQX8.
    PhylomeDBiP97481.
    TreeFamiTF317772.

    Family and domain databases

    InterProiIPR011598. bHLH_dom.
    IPR014887. HIF-1_TAD_C.
    IPR021537. HIF_alpha_subunit.
    IPR001067. Nuc_translocat.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view]
    PfamiPF11413. HIF-1. 1 hit.
    PF08778. HIF-1a_CTAD. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view]
    PRINTSiPR00785. NCTRNSLOCATR.
    SMARTiSM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view]
    SUPFAMiSSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 2 hits.
    TIGRFAMsiTIGR00229. sensory_box. 2 hits.
    PROSITEiPS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P97481-1 [UniParc]FASTAAdd to Basket

    « Hide

    MTADKEKKRS SSELRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH    50
    LDKASIMRLA ISFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA 100
    VVTQDGDMIF LSENISKFMG LTQVELTGHS IFDFTHPCDH EEIRENLTLK 150
    NGSGFGKKSK DVSTERDFFM RMKCTVTNRG RTVNLKSATW KVLHCTGQVR 200
    VYNNCPPHSS LCGSKEPLLS CLIIMCEPIQ HPSHMDIPLD SKTFLSRHSM 250
    DMKFTYCDDR ILELIGYHPE ELLGRSAYEF YHALDSENMT KSHQNLCTKG 300
    QVVSGQYRML AKHGGYVWLE TQGTVIYNPR NLQPQCIMCV NYVLSEIEKN 350
    DVVFSMDQTE SLFKPHLMAM NSIFDSSDDV AVTEKSNYLF TKLKEEPEEL 400
    AQLAPTPGDA IISLDFGSQN FDEPSAYGKA ILPPGQPWVS GLRSHSAQSE 450
    SGSLPAFTVP QADTPGNTTP SASSSSSCST PSSPEDYYSS LENPLKIEVI 500
    EKLFAMDTEP RDPGSTQTDF SELDLETLAP YIPMDGEDFQ LSPICPEEPL 550
    MPESPQPTPQ HCFSTMTSIF QPLTPGATHG PFFLDKYPQQ LESRKTESEH 600
    WPMSSIFFDA GSKGSLSPCC GQASTPLSSM GGRSNTQWPP DPPLHFGPTK 650
    WPVGDQSAES LGALPVGSSQ LEPPSAPPHV SMFKMRSAKD FGARGPYMMS 700
    PAMIALSNKL KLKRQLEYEE QAFQDTSGGD PPGTSSSHLM WKRMKSLMGG 750
    TCPLMPDKTI SANMAPDEFT QKSMRGLGQP LRHLPPPQPP STRSSGENAK 800
    TGFPPQCYAS QFQDYGPPGA QKVSGVASRL LGPSFEPYLL PELTRYDCEV 850
    NVPVPGSSTL LQGRDLLRAL DQAT 874
    Length:874
    Mass (Da):96,712
    Last modified:December 15, 1998 - v2
    Checksum:iA6FFA490AE43640C
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti25 – 251C → S in BAA20130. (PubMed:9113979)Curated
    Sequence conflicti191 – 1911K → KS in AAB41496. (PubMed:9000051)Curated
    Sequence conflicti439 – 4402VS → AA in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti463 – 4631D → G in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti654 – 6541G → V in BAA20130. (PubMed:9113979)Curated
    Sequence conflicti663 – 6631A → P in BAA20130. (PubMed:9113979)Curated
    Sequence conflicti669 – 6691S → W in AAB41496. (PubMed:9000051)Curated
    Sequence conflicti673 – 6731P → L in AAB41496. (PubMed:9000051)Curated
    Sequence conflicti678 – 6781P → L in AAB41496. (PubMed:9000051)Curated
    Sequence conflicti725 – 7251D → E in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti731 – 7311P → L in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti762 – 7621A → G in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti786 – 7861P → L in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti791 – 7911S → F in AAC12871. (PubMed:9178256)Curated
    Sequence conflicti794 – 7941S → N in AAC12871. (PubMed:9178256)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U81983 mRNA. Translation: AAB41496.1.
    D89787 mRNA. Translation: BAA20130.1.
    AF045160 mRNA. Translation: AAC12871.1.
    CCDSiCCDS37713.1.
    RefSeqiNP_034267.3. NM_010137.3.
    UniGeneiMm.1415.

    Genome annotation databases

    EnsembliENSMUST00000024954; ENSMUSP00000024954; ENSMUSG00000024140.
    GeneIDi13819.
    KEGGimmu:13819.
    UCSCiuc008duj.2. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U81983 mRNA. Translation: AAB41496.1 .
    D89787 mRNA. Translation: BAA20130.1 .
    AF045160 mRNA. Translation: AAC12871.1 .
    CCDSi CCDS37713.1.
    RefSeqi NP_034267.3. NM_010137.3.
    UniGenei Mm.1415.

    3D structure databases

    ProteinModelPortali P97481.
    SMRi P97481. Positions 16-348, 840-872.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 199458. 3 interactions.
    DIPi DIP-46109N.
    STRINGi 10090.ENSMUSP00000107892.

    PTM databases

    PhosphoSitei P97481.

    Proteomic databases

    PaxDbi P97481.
    PRIDEi P97481.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000024954 ; ENSMUSP00000024954 ; ENSMUSG00000024140 .
    GeneIDi 13819.
    KEGGi mmu:13819.
    UCSCi uc008duj.2. mouse.

    Organism-specific databases

    CTDi 2034.
    MGIi MGI:109169. Epas1.

    Phylogenomic databases

    eggNOGi NOG289264.
    GeneTreei ENSGT00730000110711.
    HOGENOMi HOG000234306.
    HOVERGENi HBG060456.
    InParanoidi P97481.
    KOi K09095.
    OMAi DPPLHFG.
    OrthoDBi EOG7JDQX8.
    PhylomeDBi P97481.
    TreeFami TF317772.

    Enzyme and pathway databases

    Reactomei REACT_199104. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_199107. Regulation of gene expression by Hypoxia-inducible Factor.
    REACT_199108. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_216222. Transcriptional regulation of pluripotent stem cells.

    Miscellaneous databases

    ChiTaRSi EPAS1. mouse.
    NextBioi 284608.
    PROi P97481.
    SOURCEi Search...

    Gene expression databases

    Bgeei P97481.
    CleanExi MM_EPAS1.
    Genevestigatori P97481.

    Family and domain databases

    InterProi IPR011598. bHLH_dom.
    IPR014887. HIF-1_TAD_C.
    IPR021537. HIF_alpha_subunit.
    IPR001067. Nuc_translocat.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view ]
    Pfami PF11413. HIF-1. 1 hit.
    PF08778. HIF-1a_CTAD. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view ]
    PRINTSi PR00785. NCTRNSLOCATR.
    SMARTi SM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view ]
    SUPFAMi SSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 2 hits.
    TIGRFAMsi TIGR00229. sensory_box. 2 hits.
    PROSITEi PS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells."
      Tian H., McKnight S.L., Russell D.W.
      Genes Dev. 11:72-82(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Brain.
    2. "A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development."
      Ema M., Taya S., Yokotani N., Sogawa K., Matsuda Y., Fujii-Kuriyama Y.
      Proc. Natl. Acad. Sci. U.S.A. 94:4273-4278(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: C57BL/6.
      Tissue: Hypothalamus and Skeletal muscle.
    3. "HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels."
      Flamme I., Froehlich T., von Reutern M., Kappel A., Damert A., Risau W.
      Mech. Dev. 63:51-60(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Brain capillary.
    4. "FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor."
      Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K.
      Genes Dev. 16:1466-1471(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 846-864, MUTAGENESIS OF PRO-530 AND ASN-851.
    5. "The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine."
      Gradin K., Takasaki C., Fujii-Kuriyama Y., Sogawa K.
      J. Biol. Chem. 277:23508-23514(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CREBBP, PHOSPHORYLATION AT THR-844, MUTAGENESIS OF THR-844.
    6. "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch."
      Lando D., Peet D.J., Whelan D.A., Gorman J.J., Whitelaw M.L.
      Science 295:858-861(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: HYDROXYLATION AT ASN-851.

    Entry informationi

    Entry nameiEPAS1_MOUSE
    AccessioniPrimary (citable) accession number: P97481
    Secondary accession number(s): O08787, O55046
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: December 15, 1998
    Last modified: October 1, 2014
    This is version 139 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3