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P97481

- EPAS1_MOUSE

UniProt

P97481 - EPAS1_MOUSE

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Protein
Endothelial PAS domain-containing protein 1
Gene
Epas1, Hif2a
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

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.

GO - Molecular functioni

  1. DNA binding Source: MGI
  2. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: MGI
  3. histone acetyltransferase binding Source: UniProtKB
  4. protein heterodimerization activity 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
Complete GO annotation...

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
Complete GO annotation...

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 Reviewed prediction

GO - Cellular componenti

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

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 1
PRO_0000127420Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei405 – 40514-hydroxyproline By similarity
Modified residuei530 – 53014-hydroxyproline By 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.
In normoxia, is hydroxylated on Asn-851 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.
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.

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.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini14 – 6754bHLH
Add
BLAST
Domaini84 – 15471PAS 1
Add
BLAST
Domaini230 – 30071PAS 2
Add
BLAST
Domaini304 – 34744PAC
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni495 – 54147NTAD
Add
BLAST
Regioni834 – 87441CTAD
Add
BLAST

Compositional bias

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

Sequence similaritiesi

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

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti25 – 251C → S in BAA20130. 1 Publication
Sequence conflicti191 – 1911K → KS in AAB41496. 1 Publication
Sequence conflicti439 – 4402VS → AA in AAC12871. 1 Publication
Sequence conflicti463 – 4631D → G in AAC12871. 1 Publication
Sequence conflicti654 – 6541G → V in BAA20130. 1 Publication
Sequence conflicti663 – 6631A → P in BAA20130. 1 Publication
Sequence conflicti669 – 6691S → W in AAB41496. 1 Publication
Sequence conflicti673 – 6731P → L in AAB41496. 1 Publication
Sequence conflicti678 – 6781P → L in AAB41496. 1 Publication
Sequence conflicti725 – 7251D → E in AAC12871. 1 Publication
Sequence conflicti731 – 7311P → L in AAC12871. 1 Publication
Sequence conflicti762 – 7621A → G in AAC12871. 1 Publication
Sequence conflicti786 – 7861P → L in AAC12871. 1 Publication
Sequence conflicti791 – 7911S → F in AAC12871. 1 Publication
Sequence conflicti794 – 7941S → N in AAC12871. 1 Publication

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...

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: September 3, 2014
This is version 138 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

Similar proteinsi