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Protein

Endothelial PAS domain-containing protein 1

Gene

EPAS1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). 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

GO - Biological processi

Keywordsi

Molecular functionActivator, Developmental protein, DNA-binding
Biological processAngiogenesis, Differentiation, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1234158 Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-1234162 Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-452723 Transcriptional regulation of pluripotent stem cells
R-HSA-8849473 PTK6 Expression
R-HSA-8951664 Neddylation
SignaLinkiQ99814
SIGNORiQ99814

Names & Taxonomyi

Protein namesi
Recommended name:
Endothelial PAS domain-containing protein 1
Short name:
EPAS-1
Alternative name(s):
Basic-helix-loop-helix-PAS protein MOP2
Class E basic helix-loop-helix protein 73
Short name:
bHLHe73
HIF-1-alpha-like factor
Short name:
HLF
Hypoxia-inducible factor 2-alpha
Short name:
HIF-2-alpha
Short name:
HIF2-alpha
Member of PAS protein 2
PAS domain-containing protein 2
Gene namesi
Name:EPAS1
Synonyms:BHLHE73, HIF2A, MOP2, PASD2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000116016.13
HGNCiHGNC:3374 EPAS1
MIMi603349 gene
neXtProtiNX_Q99814

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

Erythrocytosis, familial, 4 (ECYT4)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal platelet and leukocyte counts.
See also OMIM:611783
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067358534P → L in ECYT4; impairs interaction with EGLN1 and VHL. 1 Publication1
Natural variantiVAR_067359535M → T in ECYT4. 1 Publication1
Natural variantiVAR_067360535M → V in ECYT4; impairs interaction with EGLN1. 2 PublicationsCorresponds to variant dbSNP:rs137853037EnsemblClinVar.1
Natural variantiVAR_067361537G → R in ECYT4; impairs interaction with EGLN1 and VHL. 2 PublicationsCorresponds to variant dbSNP:rs137853036EnsemblClinVar.1
Natural variantiVAR_042443537G → W in ECYT4; gain of function; affects hydroxylation. 1 PublicationCorresponds to variant dbSNP:rs137853036EnsemblClinVar.1
Natural variantiVAR_067362540F → L in ECYT4; affects the interaction with EGLN1 and VHL. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi844C → S: Abolishes hypoxia-inducible transcriptional activation of ctaD. 1 Publication1

Keywords - Diseasei

Congenital erythrocytosis, Disease mutation

Organism-specific databases

DisGeNETi2034
MalaCardsiEPAS1
MIMi611783 phenotype
OpenTargetsiENSG00000116016
Orphaneti247511 Autosomal dominant secondary polycythemia
324299 Multiple paragangliomas associated with polycythemia
276624 Sporadic pheochromocytoma
276627 Sporadic secreting paraganglioma
PharmGKBiPA27809

Chemistry databases

ChEMBLiCHEMBL1744522

Polymorphism and mutation databases

BioMutaiEPAS1
DMDMi32470617

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001274191 – 870Endothelial PAS domain-containing protein 1Add BLAST870

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei4054-hydroxyprolineBy similarity1
Modified residuei5314-hydroxyprolineBy similarity1
Modified residuei840PhosphothreonineBy similarity1
Modified residuei847(3S)-3-hydroxyasparagineBy similarity1

Post-translational modificationi

In normoxia, is probably hydroxylated on Pro-405 and Pro-531 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-847 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.By similarity
Phosphorylated on multiple sites in the CTAD.By similarity
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.By similarity

Keywords - PTMi

Hydroxylation, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ99814
PaxDbiQ99814
PeptideAtlasiQ99814
PRIDEiQ99814
ProteomicsDBi78489

PTM databases

iPTMnetiQ99814
PhosphoSitePlusiQ99814

Expressioni

Tissue specificityi

Expressed in most tissues, with highest levels in placenta, lung and heart. Selectively expressed in endothelial cells.

Gene expression databases

BgeeiENSG00000116016 Expressed in 234 organ(s), highest expression level in visceral pleura
CleanExiHS_EPAS1
ExpressionAtlasiQ99814 baseline and differential
GenevisibleiQ99814 HS

Organism-specific databases

HPAiHPA031200
HPA069697

Interactioni

Subunit structurei

Interacts with HIF3A (By similarity). Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:16181639). Interacts with CREBBP (By similarity). Interacts with EGLN1. Interacts with VHL (PubMed:19208626).By similarity3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi108348, 111 interactors
CORUMiQ99814
DIPiDIP-32857N
ELMiQ99814
IntActiQ99814, 38 interactors
MINTiQ99814
STRINGi9606.ENSP00000263734

Chemistry databases

BindingDBiQ99814

Structurei

Secondary structure

1870
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ99814
SMRiQ99814
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ99814

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
Regioni26 – 53DNA-bindingBy similarityAdd BLAST28
Regioni171 – 192Required for heterodimer formation with ARNTBy similarityAdd BLAST22
Regioni496 – 542NTADAdd BLAST47
Regioni830 – 870CTADAdd BLAST41

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi474 – 480Poly-Ser7

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3558 Eukaryota
ENOG410YK57 LUCA
GeneTreeiENSGT00760000118788
HOGENOMiHOG000234306
HOVERGENiHBG060456
InParanoidiQ99814
KOiK09095
OMAiNNCPPHS
OrthoDBiEOG091G0486
PhylomeDBiQ99814
TreeFamiTF317772

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR014887 HIF-1_TAD_C
IPR021537 HIF_alpha_subunit
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
IPR013655 PAS_fold_3
PfamiView protein in Pfam
PF11413 HIF-1, 1 hit
PF08778 HIF-1a_CTAD, 1 hit
PF00989 PAS, 1 hit
PF08447 PAS_3, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
TIGRFAMsiTIGR00229 sensory_box, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

Q99814-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MTADKEKKRS SSERRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH
60 70 80 90 100
LDKASIMRLA ISFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA
110 120 130 140 150
VVTQDGDMIF LSENISKFMG LTQVELTGHS IFDFTHPCDH EEIRENLSLK
160 170 180 190 200
NGSGFGKKSK DMSTERDFFM RMKCTVTNRG RTVNLKSATW KVLHCTGQVK
210 220 230 240 250
VYNNCPPHNS LCGYKEPLLS CLIIMCEPIQ HPSHMDIPLD SKTFLSRHSM
260 270 280 290 300
DMKFTYCDDR ITELIGYHPE ELLGRSAYEF YHALDSENMT KSHQNLCTKG
310 320 330 340 350
QVVSGQYRML AKHGGYVWLE TQGTVIYNPR NLQPQCIMCV NYVLSEIEKN
360 370 380 390 400
DVVFSMDQTE SLFKPHLMAM NSIFDSSGKG AVSEKSNFLF TKLKEEPEEL
410 420 430 440 450
AQLAPTPGDA IISLDFGNQN FEESSAYGKA ILPPSQPWAT ELRSHSTQSE
460 470 480 490 500
AGSLPAFTVP QAAAPGSTTP SATSSSSSCS TPNSPEDYYT SLDNDLKIEV
510 520 530 540 550
IEKLFAMDTE AKDQCSTQTD FNELDLETLA PYIPMDGEDF QLSPICPEER
560 570 580 590 600
LLAENPQSTP QHCFSAMTNI FQPLAPVAPH SPFLLDKFQQ QLESKKTEPE
610 620 630 640 650
HRPMSSIFFD AGSKASLPPC CGQASTPLSS MGGRSNTQWP PDPPLHFGPT
660 670 680 690 700
KWAVGDQRTE FLGAAPLGPP VSPPHVSTFK TRSAKGFGAR GPDVLSPAMV
710 720 730 740 750
ALSNKLKLKR QLEYEEQAFQ DLSGGDPPGG STSHLMWKRM KNLRGGSCPL
760 770 780 790 800
MPDKPLSANV PNDKFTQNPM RGLGHPLRHL PLPQPPSAIS PGENSKSRFP
810 820 830 840 850
PQCYATQYQD YSLSSAHKVS GMASRLLGPS FESYLLPELT RYDCEVNVPV
860 870
LGSSTLLQGG DLLRALDQAT
Length:870
Mass (Da):96,459
Last modified:July 3, 2003 - v3
Checksum:i4838989598234FC1
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
C9J9N2C9J9N2_HUMAN
Endothelial PAS domain-containing p...
EPAS1
259Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti60A → E in AAB41495 (PubMed:9000051).Curated1
Sequence conflicti539D → G in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti601H → R in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti693D → N in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti716E → K in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti722L → P in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti765F → L in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti769P → S in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti844C → R in AAC51212 (PubMed:9079689).Curated1
Sequence conflicti847N → K in AAC51212 (PubMed:9079689).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067358534P → L in ECYT4; impairs interaction with EGLN1 and VHL. 1 Publication1
Natural variantiVAR_067359535M → T in ECYT4. 1 Publication1
Natural variantiVAR_067360535M → V in ECYT4; impairs interaction with EGLN1. 2 PublicationsCorresponds to variant dbSNP:rs137853037EnsemblClinVar.1
Natural variantiVAR_067361537G → R in ECYT4; impairs interaction with EGLN1 and VHL. 2 PublicationsCorresponds to variant dbSNP:rs137853036EnsemblClinVar.1
Natural variantiVAR_042443537G → W in ECYT4; gain of function; affects hydroxylation. 1 PublicationCorresponds to variant dbSNP:rs137853036EnsemblClinVar.1
Natural variantiVAR_067362540F → L in ECYT4; affects the interaction with EGLN1 and VHL. 1 Publication1
Natural variantiVAR_061261766T → P. Corresponds to variant dbSNP:rs59901247EnsemblClinVar.1
Natural variantiVAR_061262785P → T. Corresponds to variant dbSNP:rs61518065EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U81984 mRNA Translation: AAB41495.1
U51626 mRNA Translation: AAC51212.1
BC051338 mRNA Translation: AAH51338.1
CCDSiCCDS1825.1
RefSeqiNP_001421.2, NM_001430.4
UniGeneiHs.468410

Genome annotation databases

EnsembliENST00000263734; ENSP00000263734; ENSG00000116016
GeneIDi2034
KEGGihsa:2034
UCSCiuc002ruv.3 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U81984 mRNA Translation: AAB41495.1
U51626 mRNA Translation: AAC51212.1
BC051338 mRNA Translation: AAH51338.1
CCDSiCCDS1825.1
RefSeqiNP_001421.2, NM_001430.4
UniGeneiHs.468410

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1P97NMR-A240-350[»]
2A24NMR-A242-348[»]
3F1NX-ray1.48A239-350[»]
3F1OX-ray1.60A239-350[»]
3F1PX-ray1.17A239-350[»]
3H7WX-ray1.65A239-350[»]
3H82X-ray1.50A239-350[»]
4GHIX-ray1.50A239-350[»]
4GS9X-ray1.72A239-350[»]
4PKYX-ray3.20G239-350[»]
4XT2X-ray1.70A/C239-350[»]
5KIZNMR-A239-349[»]
5TBMX-ray1.85A239-348[»]
5UFPX-ray1.90A239-348[»]
ProteinModelPortaliQ99814
SMRiQ99814
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108348, 111 interactors
CORUMiQ99814
DIPiDIP-32857N
ELMiQ99814
IntActiQ99814, 38 interactors
MINTiQ99814
STRINGi9606.ENSP00000263734

Chemistry databases

BindingDBiQ99814
ChEMBLiCHEMBL1744522

PTM databases

iPTMnetiQ99814
PhosphoSitePlusiQ99814

Polymorphism and mutation databases

BioMutaiEPAS1
DMDMi32470617

Proteomic databases

MaxQBiQ99814
PaxDbiQ99814
PeptideAtlasiQ99814
PRIDEiQ99814
ProteomicsDBi78489

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000263734; ENSP00000263734; ENSG00000116016
GeneIDi2034
KEGGihsa:2034
UCSCiuc002ruv.3 human

Organism-specific databases

CTDi2034
DisGeNETi2034
EuPathDBiHostDB:ENSG00000116016.13
GeneCardsiEPAS1
HGNCiHGNC:3374 EPAS1
HPAiHPA031200
HPA069697
MalaCardsiEPAS1
MIMi603349 gene
611783 phenotype
neXtProtiNX_Q99814
OpenTargetsiENSG00000116016
Orphaneti247511 Autosomal dominant secondary polycythemia
324299 Multiple paragangliomas associated with polycythemia
276624 Sporadic pheochromocytoma
276627 Sporadic secreting paraganglioma
PharmGKBiPA27809
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3558 Eukaryota
ENOG410YK57 LUCA
GeneTreeiENSGT00760000118788
HOGENOMiHOG000234306
HOVERGENiHBG060456
InParanoidiQ99814
KOiK09095
OMAiNNCPPHS
OrthoDBiEOG091G0486
PhylomeDBiQ99814
TreeFamiTF317772

Enzyme and pathway databases

ReactomeiR-HSA-1234158 Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-1234162 Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-452723 Transcriptional regulation of pluripotent stem cells
R-HSA-8849473 PTK6 Expression
R-HSA-8951664 Neddylation
SignaLinkiQ99814
SIGNORiQ99814

Miscellaneous databases

ChiTaRSiEPAS1 human
EvolutionaryTraceiQ99814
GeneWikiiEPAS1
GenomeRNAii2034
PROiPR:Q99814
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000116016 Expressed in 234 organ(s), highest expression level in visceral pleura
CleanExiHS_EPAS1
ExpressionAtlasiQ99814 baseline and differential
GenevisibleiQ99814 HS

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR014887 HIF-1_TAD_C
IPR021537 HIF_alpha_subunit
IPR036638 HLH_DNA-bd_sf
IPR001067 Nuc_translocat
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
IPR013655 PAS_fold_3
PfamiView protein in Pfam
PF11413 HIF-1, 1 hit
PF08778 HIF-1a_CTAD, 1 hit
PF00989 PAS, 1 hit
PF08447 PAS_3, 1 hit
PRINTSiPR00785 NCTRNSLOCATR
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
TIGRFAMsiTIGR00229 sensory_box, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits
ProtoNetiSearch...

Entry informationi

Entry nameiEPAS1_HUMAN
AccessioniPrimary (citable) accession number: Q99814
Secondary accession number(s): Q86VA2, Q99630
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: July 3, 2003
Last modified: November 7, 2018
This is version 200 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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