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Reviewed, UniProtKB/Swiss-Prot Q99814 (EPAS1_HUMAN)

Last modified July 7, 2009. Version 104. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Endothelial PAS domain-containing protein 1
      Short name=EPAS-1
Alternative name(s):
    Member of PAS protein 2
    Basic-helix-loop-helix-PAS protein MOP2
    Hypoxia-inducible factor 2 alpha
      Short name=HIF-2 alpha
      Short name=HIF2 alpha
    HIF-1 alpha-like factor
      Short name=HLF
Gene names
Name: EPAS1
Synonyms: HIF2A, MOP2
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length870 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
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.

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

Defects in EPAS1 are the cause of erythrocytosis familial type 4 (ECYT4) [MIM:611783]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts. Ref.5

Sequence similarities

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

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

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 870870Endothelial PAS domain-containing protein 1
PRO_0000127419

Regions

Domain28 – 6841Helix-loop-helix motif
Domain84 – 15471PAS 1
Domain230 – 30071PAS 2
Domain304 – 34744PAC
DNA binding15 – 2713Basic motif
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 variant5371G → W in ECYT4; gain of function; affects hydroxylation. Ref.5
VAR_042443

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
Q99814-1 [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: 9000051] [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: 9079689] [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: 15489334] [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: 10202154] [Abstract]
Cited for: TRANSACTIVATION DOMAINS NTAD AND CTAD, INTERACTION WITH APEX, MUTAGENESIS OF CYS-844.
[5]"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: 18184961] [Abstract]
Cited for: VARIANT ECYT4 TRP-537, MASS SPECTROMETRY, CHARACTERIZATION OF VARIANT ECYT4 TRP-537.
+Additional computationally mapped references.

Cross-references

Sequence databases

U81984 mRNA. Translation: AAB41495.1.
U51626 mRNA. Translation: AAC51212.1.
BC051338 mRNA. Translation: AAH51338.1.
IPIIPI00294084.
RefSeqNP_001421.2.
UniGeneHs.468410

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1P97NMR-A240-350[»]
2A24NMR-A242-348[»]
3F1NX-ray1.48A239-350[»]
3F1OX-ray1.60A239-350[»]
3F1PX-ray1.17A239-350[»]
ModBaseSearch...

Protein-protein interaction databases

IntActQ99814. 10 interactions.

PTM databases

PhosphoSiteQ99814.

Proteomic databases

PRIDEQ99814.

Genome annotation databases

EnsemblENSG00000116016. Homo sapiens. [Contig view]
GeneID2034.
KEGGhsa:2034.
UCSCuc002ruv.1. human.

Organism-specific databases

GeneCardsGC02P046436.
H-InvDBHIX0002028.
HGNCHGNC:3374. EPAS1.
HPACAB012248.
MIM603349. gene.
611783. phenotype.
PharmGKBPA27809.
GenAtlasSearch...

Phylogenomic databases

HOGENOMQ99814.
HOVERGENQ99814.
OMAQ99814. IEKNDVV.

Enzyme and pathway databases

Pathway_Interaction_DBvegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.

Gene expression databases

ArrayExpressQ99814.
BgeeQ99814.
CleanExHS_EPAS1.
GermOnlineENSG00000116016. Homo sapiens.

Family and domain databases

InterProIPR014887. HIF-1_TAD_C.
IPR001092. HLH_basic.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013655. PAS_fold_3.
[Graphical view]
PfamPF08778. HIF-1a_CTAD. 1 hit.
PF00010. HLH. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]
PRINTSPR00785. NCTRNSLOCATR.
SMARTSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
PROSITEPS50888. HLH. 1 hit.
PS50113. PAC. False negative.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio8255.
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 7, 2009
This is version 104 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 2

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

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

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

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents