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Q99814 (EPAS1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 156. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·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):
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 names
Name:EPAS1
Synonyms:BHLHE73, HIF2A, MOP2, PASD2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length870 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 seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD.

Subunit structure

Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT. Interacts with CREBBP By similarity. Interacts with EGLN1. Interacts with VHL. Ref.4 Ref.5

Subcellular location

Nucleus Potential.

Tissue specificity

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

Post-translational modification

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.

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.

Involvement in disease

Erythrocytosis, familial, 4 (ECYT4) [MIM:611783]: An autosomal dominant disorder characterized by increased serum red blood cell mass, elevated serum hemoglobin and hematocrit, and normal platelet and leukocyte counts.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.5 Ref.6 Ref.7 Ref.8

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
   Coding sequence diversityPolymorphism
   DiseaseCongenital erythrocytosis
Disease mutation
   DomainRepeat
   LigandDNA-binding
   Molecular functionActivator
Developmental protein
   PTMHydroxylation
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processangiogenesis

Inferred from electronic annotation. Source: UniProtKB-KW

blood vessel remodeling

Inferred from electronic annotation. Source: Ensembl

cell maturation

Inferred from electronic annotation. Source: Ensembl

cellular response to hypoxia

Inferred from direct assay PubMed 11573933. Source: UniProtKB

embryonic placenta development

Inferred from electronic annotation. Source: Ensembl

erythrocyte differentiation

Inferred from electronic annotation. Source: Ensembl

lung development

Inferred from electronic annotation. Source: Ensembl

mitochondrion organization

Inferred from electronic annotation. Source: Ensembl

myoblast fate commitment

Inferred from sequence or structural similarity. Source: BHF-UCL

norepinephrine metabolic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay PubMed 11573933. Source: UniProtKB

regulation of heart rate

Inferred from electronic annotation. Source: Ensembl

regulation of transcription from RNA polymerase II promoter in response to hypoxia

Traceable author statement. Source: Reactome

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

Inferred from electronic annotation. Source: Ensembl

response to hypoxia

Inferred from direct assay PubMed 11782478. Source: MGI

signal transduction

Traceable author statement Ref.2. Source: ProtInc

surfactant homeostasis

Inferred from electronic annotation. Source: Ensembl

transcription from RNA polymerase II promoter

Traceable author statement Ref.2. Source: ProtInc

visual perception

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

nucleoplasm

Traceable author statement. Source: Reactome

transcription factor complex

Inferred from direct assay Ref.1. Source: MGI

   Molecular_functionDNA binding

Inferred from genetic interaction Ref.1. Source: MGI

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

Inferred from electronic annotation. Source: Ensembl

histone acetyltransferase binding

Inferred from physical interaction PubMed 15261140. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.5. Source: UniProtKB

protein heterodimerization activity

Inferred from physical interaction Ref.2. Source: BHF-UCL

signal transducer activity

Inferred from electronic annotation. Source: InterPro

transcription factor binding

Inferred from physical interaction Ref.2. Source: BHF-UCL

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 870870Endothelial PAS domain-containing protein 1
PRO_0000127419

Regions

Domain14 – 6754bHLH
Domain84 – 15471PAS 1
Domain230 – 30071PAS 2
Domain304 – 34744PAC
Region496 – 54247NTAD
Region830 – 87041CTAD
Compositional bias474 – 4807Poly-Ser

Amino acid modifications

Modified residue40514-hydroxyproline By similarity
Modified residue53114-hydroxyproline By similarity
Modified residue8401Phosphothreonine By similarity
Modified residue8471(3S)-3-hydroxyasparagine By similarity

Natural variations

Natural variant5341P → L in ECYT4; impairs interaction with EGLN1 and VHL. Ref.5
VAR_067358
Natural variant5351M → T in ECYT4. Ref.8
VAR_067359
Natural variant5351M → V in ECYT4; impairs interaction with EGLN1. Ref.5 Ref.6
VAR_067360
Natural variant5371G → R in ECYT4; impairs interaction with EGLN1 and VHL. Ref.5 Ref.6
VAR_067361
Natural variant5371G → W in ECYT4; gain of function; affects hydroxylation. Ref.7
VAR_042443
Natural variant5401F → L in ECYT4; affects the interaction with EGLN1 and VHL. Ref.8
VAR_067362
Natural variant7661T → P.
Corresponds to variant rs59901247 [ dbSNP | Ensembl ].
VAR_061261
Natural variant7851P → T.
Corresponds to variant rs61518065 [ dbSNP | Ensembl ].
VAR_061262

Experimental info

Mutagenesis8441C → S: Abolishes hypoxia-inducible transcriptional activation of ctaD. Ref.4
Sequence conflict601A → E in AAB41495. Ref.1
Sequence conflict5391D → G in AAC51212. Ref.2
Sequence conflict6011H → R in AAC51212. Ref.2
Sequence conflict6931D → N in AAC51212. Ref.2
Sequence conflict7161E → K in AAC51212. Ref.2
Sequence conflict7221L → P in AAC51212. Ref.2
Sequence conflict7651F → L in AAC51212. Ref.2
Sequence conflict7691P → S in AAC51212. Ref.2
Sequence conflict8441C → R in AAC51212. Ref.2
Sequence conflict8471N → K in AAC51212. Ref.2

Secondary structure

......................... 870
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q99814 [UniParc].

Last modified July 3, 2003. Version 3.
Checksum: 4838989598234FC1

FASTA87096,459
        10         20         30         40         50         60 
MTADKEKKRS SSERRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH LDKASIMRLA 

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

       130        140        150        160        170        180 
LTQVELTGHS IFDFTHPCDH EEIRENLSLK NGSGFGKKSK DMSTERDFFM RMKCTVTNRG 

       190        200        210        220        230        240 
RTVNLKSATW KVLHCTGQVK VYNNCPPHNS LCGYKEPLLS CLIIMCEPIQ HPSHMDIPLD 

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

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

       370        380        390        400        410        420 
SLFKPHLMAM NSIFDSSGKG AVSEKSNFLF TKLKEEPEEL AQLAPTPGDA IISLDFGNQN 

       430        440        450        460        470        480 
FEESSAYGKA ILPPSQPWAT ELRSHSTQSE AGSLPAFTVP QAAAPGSTTP SATSSSSSCS 

       490        500        510        520        530        540 
TPNSPEDYYT SLDNDLKIEV IEKLFAMDTE AKDQCSTQTD FNELDLETLA PYIPMDGEDF 

       550        560        570        580        590        600 
QLSPICPEER LLAENPQSTP QHCFSAMTNI FQPLAPVAPH SPFLLDKFQQ QLESKKTEPE 

       610        620        630        640        650        660 
HRPMSSIFFD AGSKASLPPC CGQASTPLSS MGGRSNTQWP PDPPLHFGPT KWAVGDQRTE 

       670        680        690        700        710        720 
FLGAAPLGPP VSPPHVSTFK TRSAKGFGAR GPDVLSPAMV ALSNKLKLKR QLEYEEQAFQ 

       730        740        750        760        770        780 
DLSGGDPPGG STSHLMWKRM KNLRGGSCPL MPDKPLSANV PNDKFTQNPM RGLGHPLRHL 

       790        800        810        820        830        840 
PLPQPPSAIS PGENSKSRFP PQCYATQYQD YSLSSAHKVS GMASRLLGPS FESYLLPELT 

       850        860        870 
RYDCEVNVPV LGSSTLLQGG DLLRALDQAT 

« Hide

References

« Hide 'large scale' 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].
[2]"Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway."
Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z., Pray-Grant M., Perdew G.H., Bradfield C.A.
J. Biol. Chem. 272:8581-8593(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Hepatoma.
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Eye.
[4]"Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300."
Ema M., Hirota K., Mimura J., Abe H., Yodoi J., Sogawa K., Poellinger L., Fujii-Kuriyama Y.
EMBO J. 18:1905-1914(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: TRANSACTIVATION DOMAINS NTAD AND CTAD, INTERACTION WITH APEX, MUTAGENESIS OF CYS-844.
[5]"Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline."
Furlow P.W., Percy M.J., Sutherland S., Bierl C., McMullin M.F., Master S.R., Lappin T.R., Lee F.S.
J. Biol. Chem. 284:9050-9058(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EGLN1 AND VHL, VARIANT ECYT4 LEU-534, CHARACTERIZATION OF VARIANTS ECYT4 LEU-534; VAL-535 AND ARG-537.
[6]"Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis."
Percy M.J., Beer P.A., Campbell G., Dekker A.W., Green A.R., Oscier D., Rainey M.G., van Wijk R., Wood M., Lappin T.R., McMullin M.F., Lee F.S.
Blood 111:5400-5402(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ECYT4 VAL-535 AND ARG-537.
[7]"A gain-of-function mutation in the HIF2A gene in familial erythrocytosis."
Percy M.J., Furlow P.W., Lucas G.S., Li X., Lappin T.R., McMullin M.F., Lee F.S.
N. Engl. J. Med. 358:162-168(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ECYT4 TRP-537, IDENTIFICATION BY MASS SPECTROMETRY, CHARACTERIZATION OF VARIANT ECYT4 TRP-537.
[8]"Two new mutations in the HIF2A gene associated with erythrocytosis."
Percy M.J., Chung Y.J., Harrison C., Mercieca J., Hoffbrand A.V., Dinardo C.L., Santos P.C., Fonseca G.H., Gualandro S.F., Pereira A.C., Lappin T.R., McMullin M.F., Lee F.S.
Am. J. Hematol. 87:439-442(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ECYT4 THR-535 AND LEU-540, CHARACTERIZATION OF VARIANT ECYT4 LEU-540.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U81984 mRNA. Translation: AAB41495.1.
U51626 mRNA. Translation: AAC51212.1.
BC051338 mRNA. Translation: AAH51338.1.
CCDSCCDS1825.1.
RefSeqNP_001421.2. NM_001430.4.
UniGeneHs.468410.

3D structure databases

PDBe
RCSB-PDB
PDBj
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[»]
ProteinModelPortalQ99814.
SMRQ99814. Positions 16-348, 836-868.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108348. 103 interactions.
DIPDIP-32857N.
IntActQ99814. 29 interactions.
MINTMINT-1199606.
STRING9606.ENSP00000263734.

Chemistry

BindingDBQ99814.
ChEMBLCHEMBL1744522.

PTM databases

PhosphoSiteQ99814.

Polymorphism databases

DMDM32470617.

Proteomic databases

MaxQBQ99814.
PaxDbQ99814.
PRIDEQ99814.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000263734; ENSP00000263734; ENSG00000116016.
GeneID2034.
KEGGhsa:2034.
UCSCuc002ruv.3. human.

Organism-specific databases

CTD2034.
GeneCardsGC02P046436.
HGNCHGNC:3374. EPAS1.
HPACAB012248.
MIM603349. gene.
611783. phenotype.
neXtProtNX_Q99814.
Orphanet247511. Autosomal dominant secondary polycythemia.
324299. Multiple paragangliomas associated with polycythemia.
276624. Sporadic pheochromocytoma.
276627. Sporadic secreting paraganglioma.
PharmGKBPA27809.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG289264.
HOGENOMHOG000234306.
HOVERGENHBG060456.
InParanoidQ99814.
KOK09095.
OMADPPLHFG.
OrthoDBEOG7JDQX8.
PhylomeDBQ99814.
TreeFamTF317772.

Enzyme and pathway databases

ReactomeREACT_111045. Developmental Biology.
REACT_120956. Cellular responses to stress.
SignaLinkQ99814.

Gene expression databases

ArrayExpressQ99814.
BgeeQ99814.
CleanExHS_EPAS1.
GenevestigatorQ99814.

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. human.
EvolutionaryTraceQ99814.
GeneWikiEPAS1.
GenomeRNAi2034.
NextBio8255.
PROQ99814.
SOURCESearch...

Entry information

Entry nameEPAS1_HUMAN
AccessionPrimary (citable) accession number: Q99814
Secondary accession number(s): Q86VA2, Q99630
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: July 3, 2003
Last modified: July 9, 2014
This is version 156 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM