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Protein

Endothelial PAS domain-containing protein 1

Gene

Epas1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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 CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD (By similarity).By similarity

GO - Molecular functioni

  • DNA binding Source: MGI
  • histone acetyltransferase binding Source: UniProtKB
  • protein heterodimerization activity Source: MGI
  • sequence-specific DNA binding Source: Ensembl
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding Source: MGI
  • transcription factor activity, sequence-specific DNA binding Source: MGI
  • transcription factor binding Source: MGI

GO - Biological processi

  • angiogenesis Source: MGI
  • blood vessel remodeling Source: MGI
  • cell differentiation Source: MGI
  • cell maturation Source: MGI
  • cellular response to hypoxia Source: UniProtKB
  • embryonic placenta development Source: MGI
  • erythrocyte differentiation Source: MGI
  • hemopoiesis Source: MGI
  • iron ion homeostasis Source: MGI
  • lung development Source: MGI
  • mitochondrion organization Source: MGI
  • myoblast fate commitment Source: BHF-UCL
  • norepinephrine metabolic process Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • regulation of heart rate Source: MGI
  • regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: MGI
  • response to hypoxia Source: MGI
  • response to oxidative stress Source: MGI
  • surfactant homeostasis Source: MGI
  • 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

ReactomeiR-MMU-1234158. Regulation of gene expression by Hypoxia-inducible Factor.
R-MMU-1234162. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
R-MMU-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

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
Proteomesi
  • UP000000589 Componenti: Chromosome 17

Organism-specific databases

MGIiMGI:109169. Epas1.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: MGI
  • nuclear speck Source: UniProtKB
  • nucleus Source: UniProtKB
  • transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi530P → A: Confers transcriptional activity at normoxia; when associated with A-851. 1 Publication1
Mutagenesisi844T → A: Decreases interaction with CREBBP. 1 Publication1
Mutagenesisi851N → A: Confers transcriptional activity at normoxia; when associated with A-530. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001274201 – 874Endothelial PAS domain-containing protein 1Add BLAST874

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei4054-hydroxyprolineBy similarity1
Modified residuei5304-hydroxyprolineBy similarity1
Modified residuei844Phosphothreonine1 Publication1
Modified residuei851(3S)-3-hydroxyasparagine1 Publication1

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

iPTMnetiP97481.
PhosphoSitePlusiP97481.

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

BgeeiENSMUSG00000024140.
CleanExiMM_EPAS1.
GenevisibleiP97481. MM.

Interactioni

Subunit structurei

Interacts with HIF3A isoform 2 (PubMed:21546903). Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT. Interacts with CREBBP.2 Publications

GO - Molecular functioni

  • histone acetyltransferase binding Source: UniProtKB
  • protein heterodimerization activity Source: MGI
  • transcription factor binding Source: MGI

Protein-protein interaction databases

BioGridi199458. 3 interactors.
DIPiDIP-46109N.
STRINGi10090.ENSMUSP00000024954.

Structurei

Secondary structure

1874
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi27 – 39Combined sources13
Beta strandi41 – 43Combined sources3
Helixi45 – 48Combined sources4
Helixi53 – 74Combined sources22
Helixi88 – 94Combined sources7
Beta strandi96 – 103Combined sources8
Beta strandi107 – 111Combined sources5
Helixi115 – 119Combined sources5
Helixi123 – 126Combined sources4
Helixi131 – 134Combined sources4
Helixi137 – 147Combined sources11
Beta strandi165 – 174Combined sources10
Helixi185 – 187Combined sources3
Beta strandi189 – 200Combined sources12
Beta strandi221 – 228Combined sources8
Beta strandi243 – 248Combined sources6
Beta strandi253 – 257Combined sources5
Helixi260 – 265Combined sources6
Helixi269 – 272Combined sources4
Helixi277 – 280Combined sources4
Helixi283 – 299Combined sources17
Beta strandi300 – 303Combined sources4
Beta strandi307 – 310Combined sources4
Beta strandi314 – 327Combined sources14
Turni329 – 331Combined sources3
Beta strandi334 – 343Combined sources10
Helixi356 – 359Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4ZP4X-ray2.35B/D3-361[»]
4ZPHX-ray2.80B/D3-361[»]
4ZPKX-ray3.60B3-361[»]
4ZQDX-ray2.87B/D3-361[»]
ProteinModelPortaliP97481.
SMRiP97481.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini14 – 67bHLHPROSITE-ProRule annotationAdd BLAST54
Domaini84 – 154PAS 1PROSITE-ProRule annotationAdd BLAST71
Domaini230 – 300PAS 2PROSITE-ProRule annotationAdd BLAST71
Domaini304 – 347PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni495 – 541NTADAdd BLAST47
Regioni834 – 874CTADAdd BLAST41

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi471 – 479Poly-Ser9

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

eggNOGiKOG3558. Eukaryota.
ENOG410YK57. LUCA.
GeneTreeiENSGT00760000118788.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiP97481.
KOiK09095.
OMAiDPPLHFG.
OrthoDBiEOG091G0486.
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.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 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

        10         20         30         40         50
MTADKEKKRS SSELRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH
60 70 80 90 100
LDKASIMRLA ISFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA
110 120 130 140 150
VVTQDGDMIF LSENISKFMG LTQVELTGHS IFDFTHPCDH EEIRENLTLK
160 170 180 190 200
NGSGFGKKSK DVSTERDFFM RMKCTVTNRG RTVNLKSATW KVLHCTGQVR
210 220 230 240 250
VYNNCPPHSS LCGSKEPLLS CLIIMCEPIQ HPSHMDIPLD SKTFLSRHSM
260 270 280 290 300
DMKFTYCDDR ILELIGYHPE ELLGRSAYEF YHALDSENMT KSHQNLCTKG
310 320 330 340 350
QVVSGQYRML AKHGGYVWLE TQGTVIYNPR NLQPQCIMCV NYVLSEIEKN
360 370 380 390 400
DVVFSMDQTE SLFKPHLMAM NSIFDSSDDV AVTEKSNYLF TKLKEEPEEL
410 420 430 440 450
AQLAPTPGDA IISLDFGSQN FDEPSAYGKA ILPPGQPWVS GLRSHSAQSE
460 470 480 490 500
SGSLPAFTVP QADTPGNTTP SASSSSSCST PSSPEDYYSS LENPLKIEVI
510 520 530 540 550
EKLFAMDTEP RDPGSTQTDF SELDLETLAP YIPMDGEDFQ LSPICPEEPL
560 570 580 590 600
MPESPQPTPQ HCFSTMTSIF QPLTPGATHG PFFLDKYPQQ LESRKTESEH
610 620 630 640 650
WPMSSIFFDA GSKGSLSPCC GQASTPLSSM GGRSNTQWPP DPPLHFGPTK
660 670 680 690 700
WPVGDQSAES LGALPVGSSQ LEPPSAPPHV SMFKMRSAKD FGARGPYMMS
710 720 730 740 750
PAMIALSNKL KLKRQLEYEE QAFQDTSGGD PPGTSSSHLM WKRMKSLMGG
760 770 780 790 800
TCPLMPDKTI SANMAPDEFT QKSMRGLGQP LRHLPPPQPP STRSSGENAK
810 820 830 840 850
TGFPPQCYAS QFQDYGPPGA QKVSGVASRL LGPSFEPYLL PELTRYDCEV
860 870
NVPVPGSSTL LQGRDLLRAL DQAT
Length:874
Mass (Da):96,712
Last modified:December 15, 1998 - v2
Checksum:iA6FFA490AE43640C
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti25C → S in BAA20130 (PubMed:9113979).Curated1
Sequence conflicti191K → KS in AAB41496 (PubMed:9000051).Curated1
Sequence conflicti439 – 440VS → AA in AAC12871 (PubMed:9178256).Curated2
Sequence conflicti463D → G in AAC12871 (PubMed:9178256).Curated1
Sequence conflicti654G → V in BAA20130 (PubMed:9113979).Curated1
Sequence conflicti663A → P in BAA20130 (PubMed:9113979).Curated1
Sequence conflicti669S → W in AAB41496 (PubMed:9000051).Curated1
Sequence conflicti673P → L in AAB41496 (PubMed:9000051).Curated1
Sequence conflicti678P → L in AAB41496 (PubMed:9000051).Curated1
Sequence conflicti725D → E in AAC12871 (PubMed:9178256).Curated1
Sequence conflicti731P → L in AAC12871 (PubMed:9178256).Curated1
Sequence conflicti762A → G in AAC12871 (PubMed:9178256).Curated1
Sequence conflicti786P → L in AAC12871 (PubMed:9178256).Curated1
Sequence conflicti791S → F in AAC12871 (PubMed:9178256).Curated1
Sequence conflicti794S → N in AAC12871 (PubMed:9178256).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4ZP4X-ray2.35B/D3-361[»]
4ZPHX-ray2.80B/D3-361[»]
4ZPKX-ray3.60B3-361[»]
4ZQDX-ray2.87B/D3-361[»]
ProteinModelPortaliP97481.
SMRiP97481.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi199458. 3 interactors.
DIPiDIP-46109N.
STRINGi10090.ENSMUSP00000024954.

PTM databases

iPTMnetiP97481.
PhosphoSitePlusiP97481.

Proteomic databases

PaxDbiP97481.
PRIDEiP97481.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi2034.
MGIiMGI:109169. Epas1.

Phylogenomic databases

eggNOGiKOG3558. Eukaryota.
ENOG410YK57. LUCA.
GeneTreeiENSGT00760000118788.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiP97481.
KOiK09095.
OMAiDPPLHFG.
OrthoDBiEOG091G0486.
PhylomeDBiP97481.
TreeFamiTF317772.

Enzyme and pathway databases

ReactomeiR-MMU-1234158. Regulation of gene expression by Hypoxia-inducible Factor.
R-MMU-1234162. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
R-MMU-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

Miscellaneous databases

ChiTaRSiEpas1. mouse.
PROiP97481.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000024140.
CleanExiMM_EPAS1.
GenevisibleiP97481. MM.

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.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 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]
ProtoNetiSearch...

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: November 2, 2016
This is version 156 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

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.