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P97481 (EPAS1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Epas1
Synonyms:Hif2a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length874 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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.

Subunit structure

Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT. Interacts with CREBPB. Ref.5

Subcellular location

Nucleus Potential.

Tissue specificity

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 stage

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.

Post-translational modification

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. Ref.5

The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.

Sequence similarities

Contains 1 bHLH (basic helix-loop-helix) domain.

Contains 1 PAC (PAS-associated C-terminal) domain.

Contains 2 PAS (PER-ARNT-SIM) domains.

Ontologies

Keywords
   Biological processAngiogenesis
Differentiation
Transcription
Transcription regulation
   Cellular componentNucleus
   DomainRepeat
   LigandDNA-binding
   Molecular functionActivator
Developmental protein
   PTMHydroxylation
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processangiogenesis

Inferred from mutant phenotype PubMed 12053176PubMed 15728559PubMed 15851592. Source: MGI

blood vessel remodeling

Inferred from mutant phenotype PubMed 10880563. Source: MGI

cell differentiation

Inferred from genetic interaction PubMed 16287860. Source: MGI

cell maturation

Inferred from mutant phenotype PubMed 12053176. Source: MGI

cellular response to hypoxia

Inferred from sequence or structural similarity. Source: UniProtKB

embryonic placenta development

Inferred from genetic interaction PubMed 16287860. Source: MGI

erythrocyte differentiation

Inferred from mutant phenotype PubMed 17284606. Source: MGI

hemopoiesis

Inferred from mutant phenotype PubMed 12750163PubMed 15626745. Source: MGI

lung development

Inferred from mutant phenotype PubMed 12053176. Source: MGI

mitochondrion organization

Inferred from mutant phenotype PubMed 14608355. Source: MGI

myoblast fate commitment

Inferred from mutant phenotype PubMed 21106753. Source: BHF-UCL

norepinephrine metabolic process

Inferred from mutant phenotype PubMed 9808618. Source: MGI

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 12464608PubMed 17322295. Source: MGI

regulation of heart rate

Inferred from mutant phenotype PubMed 9808618. Source: MGI

regulation of transcription from RNA polymerase II promoter in response to oxidative stress

Inferred from direct assay PubMed 14608355. Source: MGI

response to hypoxia

Inferred from mutant phenotype PubMed 15626745. Source: MGI

response to oxidative stress

Inferred from mutant phenotype PubMed 14608355. Source: MGI

surfactant homeostasis

Inferred from mutant phenotype PubMed 12053176. Source: MGI

visual perception

Inferred from mutant phenotype PubMed 15728559. Source: MGI

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 12832481. Source: MGI

nucleus

Inferred from direct assay PubMed 12464608. Source: MGI

transcription factor complex

Inferred from direct assay PubMed 12464608. Source: MGI

   Molecular_functionDNA binding

Inferred from direct assay PubMed 12464608PubMed 17404621. Source: MGI

RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription

Inferred from direct assay PubMed 21856340. Source: MGI

histone acetyltransferase binding

Inferred from sequence or structural similarity. Source: UniProtKB

protein heterodimerization activity

Inferred from physical interaction Ref.2. Source: MGI

sequence-specific DNA binding

Inferred from electronic annotation. Source: Ensembl

sequence-specific DNA binding transcription factor activity

Inferred from direct assay PubMed 12464608. Source: MGI

signal transducer activity

Inferred from electronic annotation. Source: InterPro

transcription factor binding

Inferred from physical interaction PubMed 12464608. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 874874Endothelial PAS domain-containing protein 1
PRO_0000127420

Regions

Domain14 – 6754bHLH
Domain84 – 15471PAS 1
Domain230 – 30071PAS 2
Domain304 – 34744PAC
Region495 – 54147NTAD
Region834 – 87441CTAD
Compositional bias471 – 4799Poly-Ser

Amino acid modifications

Modified residue40514-hydroxyproline By similarity
Modified residue53014-hydroxyproline By similarity
Modified residue8441Phosphothreonine Ref.5
Modified residue8511(3S)-3-hydroxyasparagine Ref.6

Experimental info

Mutagenesis5301P → A: Confers transcriptional activity at normoxia; when associated with A-851. Ref.4
Mutagenesis8441T → A: Decreases interaction with CREBBP. Ref.5
Mutagenesis8511N → A: Confers transcriptional activity at normoxia; when associated with A-530. Ref.4
Sequence conflict251C → S in BAA20130. Ref.2
Sequence conflict1911K → KS in AAB41496. Ref.1
Sequence conflict439 – 4402VS → AA in AAC12871. Ref.3
Sequence conflict4631D → G in AAC12871. Ref.3
Sequence conflict6541G → V in BAA20130. Ref.2
Sequence conflict6631A → P in BAA20130. Ref.2
Sequence conflict6691S → W in AAB41496. Ref.1
Sequence conflict6731P → L in AAB41496. Ref.1
Sequence conflict6781P → L in AAB41496. Ref.1
Sequence conflict7251D → E in AAC12871. Ref.3
Sequence conflict7311P → L in AAC12871. Ref.3
Sequence conflict7621A → G in AAC12871. Ref.3
Sequence conflict7861P → L in AAC12871. Ref.3
Sequence conflict7911S → F in AAC12871. Ref.3
Sequence conflict7941S → N in AAC12871. Ref.3

Sequences

Sequence LengthMass (Da)Tools
P97481 [UniParc].

Last modified December 15, 1998. Version 2.
Checksum: A6FFA490AE43640C

FASTA87496,712
        10         20         30         40         50         60 
MTADKEKKRS SSELRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH LDKASIMRLA 

        70         80         90        100        110        120 
ISFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA VVTQDGDMIF LSENISKFMG 

       130        140        150        160        170        180 
LTQVELTGHS IFDFTHPCDH EEIRENLTLK NGSGFGKKSK DVSTERDFFM RMKCTVTNRG 

       190        200        210        220        230        240 
RTVNLKSATW KVLHCTGQVR VYNNCPPHSS LCGSKEPLLS CLIIMCEPIQ HPSHMDIPLD 

       250        260        270        280        290        300 
SKTFLSRHSM DMKFTYCDDR ILELIGYHPE ELLGRSAYEF YHALDSENMT KSHQNLCTKG 

       310        320        330        340        350        360 
QVVSGQYRML AKHGGYVWLE TQGTVIYNPR NLQPQCIMCV NYVLSEIEKN DVVFSMDQTE 

       370        380        390        400        410        420 
SLFKPHLMAM NSIFDSSDDV AVTEKSNYLF TKLKEEPEEL AQLAPTPGDA IISLDFGSQN 

       430        440        450        460        470        480 
FDEPSAYGKA ILPPGQPWVS GLRSHSAQSE SGSLPAFTVP QADTPGNTTP SASSSSSCST 

       490        500        510        520        530        540 
PSSPEDYYSS LENPLKIEVI EKLFAMDTEP RDPGSTQTDF SELDLETLAP YIPMDGEDFQ 

       550        560        570        580        590        600 
LSPICPEEPL MPESPQPTPQ HCFSTMTSIF QPLTPGATHG PFFLDKYPQQ LESRKTESEH 

       610        620        630        640        650        660 
WPMSSIFFDA GSKGSLSPCC GQASTPLSSM GGRSNTQWPP DPPLHFGPTK WPVGDQSAES 

       670        680        690        700        710        720 
LGALPVGSSQ LEPPSAPPHV SMFKMRSAKD FGARGPYMMS PAMIALSNKL KLKRQLEYEE 

       730        740        750        760        770        780 
QAFQDTSGGD PPGTSSSHLM WKRMKSLMGG TCPLMPDKTI SANMAPDEFT QKSMRGLGQP 

       790        800        810        820        830        840 
LRHLPPPQPP STRSSGENAK TGFPPQCYAS QFQDYGPPGA QKVSGVASRL LGPSFEPYLL 

       850        860        870 
PELTRYDCEV NVPVPGSSTL LQGRDLLRAL DQAT 

« Hide

References

[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U81983 mRNA. Translation: AAB41496.1.
D89787 mRNA. Translation: BAA20130.1.
AF045160 mRNA. Translation: AAC12871.1.
RefSeqNP_034267.3. NM_010137.3.
UniGeneMm.1415.

3D structure databases

ProteinModelPortalP97481.
SMRP97481. Positions 16-348, 840-872.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid199458. 3 interactions.
DIPDIP-46109N.
STRING10090.ENSMUSP00000107892.

PTM databases

PhosphoSiteP97481.

Proteomic databases

PaxDbP97481.
PRIDEP97481.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000024954; ENSMUSP00000024954; ENSMUSG00000024140.
GeneID13819.
KEGGmmu:13819.
UCSCuc008duj.2. mouse.

Organism-specific databases

CTD2034.
MGIMGI:109169. Epas1.

Phylogenomic databases

eggNOGNOG289264.
GeneTreeENSGT00730000110711.
HOGENOMHOG000234306.
HOVERGENHBG060456.
InParanoidP97481.
KOK09095.
OMALHFGPTK.
OrthoDBEOG7JDQX8.
PhylomeDBP97481.
TreeFamTF317772.

Gene expression databases

BgeeP97481.
CleanExMM_EPAS1.
GenevestigatorP97481.

Family and domain databases

InterProIPR011598. bHLH_dom.
IPR014887. HIF-1_TAD_C.
IPR021537. HIF_alpha_subunit.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
[Graphical view]
PfamPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF00989. PAS. 1 hit.
[Graphical view]
PRINTSPR00785. NCTRNSLOCATR.
SMARTSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsTIGR00229. sensory_box. 2 hits.
PROSITEPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSEPAS1. mouse.
NextBio284608.
PROP97481.
SOURCESearch...

Entry information

Entry nameEPAS1_MOUSE
AccessionPrimary (citable) accession number: P97481
Secondary accession number(s): O08787, O55046
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: December 15, 1998
Last modified: April 16, 2014
This is version 135 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot