Q99814 (EPAS1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	EPAS1
Synonyms:	BHLHE73, HIF2A, MOP2, PASD2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	870 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Familial erythrocytosis 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 process	Angiogenesis Differentiation Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Disease	Congenital erythrocytosis Disease mutation
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Hydroxylation Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW blood vessel remodeling Inferred from electronic annotation. Source: Compara cell maturation Inferred from electronic annotation. Source: Compara embryonic placenta development Inferred from electronic annotation. Source: Compara erythrocyte differentiation Inferred from electronic annotation. Source: Compara lung development Inferred from electronic annotation. Source: Compara mitochondrion organization Inferred from electronic annotation. Source: Compara myoblast cell fate commitment Inferred from sequence or structural similarity. Source: BHF-UCL norepinephrine metabolic process Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from genetic interaction Ref.1PubMed 9576906. Source: MGI regulation of heart rate Inferred from electronic annotation. Source: Compara 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: Compara signal transduction Traceable author statement Ref.2. Source: ProtInc surfactant homeostasis Inferred from electronic annotation. Source: Compara transcription from RNA polymerase II promoter Traceable author statement Ref.2. Source: ProtInc visual perception Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Traceable author statement. Source: Reactome transcription factor complex Inferred from direct assay Ref.1. Source: MGI
Molecular_function	DNA 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: Compara signal transducer activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
BBS4	Q96RK4	2	EBI-447470,EBI-1805814
EIF3E	P60228	10	EBI-447470,EBI-347740
MAX	P61244	2	EBI-447470,EBI-751711

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 870

870

Endothelial PAS domain-containing protein 1

PRO_0000127419

Regions

Domain

14 – 67

54

bHLH

Domain

84 – 154

71

PAS 1

Domain

230 – 300

71

PAS 2

Domain

304 – 347

44

PAC

Region

496 – 542

47

NTAD

Region

830 – 870

41

CTAD

Compositional bias

474 – 480

7

Poly-Ser

Amino acid modifications

Modified residue

405

1

4-hydroxyproline By similarity

Modified residue

531

1

4-hydroxyproline By similarity

Modified residue

840

1

Phosphothreonine By similarity

Modified residue

847

1

(3S)-3-hydroxyasparagine By similarity

Natural variations

Natural variant

534

1

P → L in ECYT4; impairs interaction with EGLN1 and VHL. Ref.5

VAR_067358

Natural variant

535

1

M → T in ECYT4. Ref.8

VAR_067359

Natural variant

535

1

M → V in ECYT4; impairs interaction with EGLN1. Ref.5 Ref.6

VAR_067360

Natural variant

537

1

G → R in ECYT4; impairs interaction with EGLN1 and VHL. Ref.5 Ref.6

VAR_067361

Natural variant

537

1

G → W in ECYT4; gain of function; affects hydroxylation. Ref.7

VAR_042443

Natural variant

540

1

F → L in ECYT4; affects the interaction with EGLN1 and VHL. Ref.8

VAR_067362

Natural variant

766

1

T → P.
Corresponds to variant rs59901247 [ dbSNP | Ensembl ].

VAR_061261

Natural variant

785

1

P → T.
Corresponds to variant rs61518065 [ dbSNP | Ensembl ].

VAR_061262

Experimental info

Mutagenesis

844

1

C → S: Abolishes hypoxia-inducible transcriptional activation of ctaD. Ref.4

Sequence conflict

60

1

A → E in AAB41495. Ref.1

Sequence conflict

539

1

D → G in AAC51212. Ref.2

Sequence conflict

601

1

H → R in AAC51212. Ref.2

Sequence conflict

693

1

D → N in AAC51212. Ref.2

Sequence conflict

716

1

E → K in AAC51212. Ref.2

Sequence conflict

722

1

L → P in AAC51212. Ref.2

Sequence conflict

765

1

F → L in AAC51212. Ref.2

Sequence conflict

769

1

P → S in AAC51212. Ref.2

Sequence conflict

844

1

C → R in AAC51212. Ref.2

Sequence conflict

847

1

N → K in AAC51212. Ref.2

Secondary structure

1

.

.

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.

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.

.

.

.

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.

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.

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870

Helix Strand Turn

Details...

Helix

240 – 242

3

Beta strand

243 – 248

6

Turn

250 – 252

3

Beta strand

253 – 257

5

Helix

260 – 265

6

Helix

269 – 272

4

Helix

277 – 280

4

Helix

283 – 285

3

Helix

286 – 299

14

Beta strand

300 – 303

4

Beta strand

307 – 310

4

Beta strand

314 – 327

14

Turn

329 – 331

3

Beta strand

334 – 343

10

Sequences

	Sequence		Length	Mass (Da)
	Q99814 [UniParc]. Last modified July 3, 2003. Version 3. Checksum: 4838989598234FC1	FASTA	870	96,459
	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

References

	« Hide 'large scale' referencesShow '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, 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.

IPI

IPI00294084.

RefSeq

NP_001421.2. NM_001430.4.

UniGene

Hs.468410.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1P97	NMR	-	A	240-350	[»]
2A24	NMR	-	A	242-348	[»]
3F1N	X-ray	1.48	A	239-350	[»]
3F1O	X-ray	1.60	A	239-350	[»]
3F1P	X-ray	1.17	A	239-350	[»]
3H7W	X-ray	1.65	A	239-350	[»]
3H82	X-ray	1.50	A	239-350	[»]
4GHI	X-ray	1.50	A	239-350	[»]

ProteinModelPortal

Q99814.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-32857N.

IntAct

Q99814. 22 interactions.

MINT

MINT-1199606.

STRING

9606.ENSP00000263734.

PTM databases

PhosphoSite

Q99814.

Polymorphism databases

DMDM

32470617.

Proteomic databases

PaxDb

Q99814.

PRIDE

Q99814.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000263734; ENSP00000263734; ENSG00000116016.

GeneID

2034.

KEGG

hsa:2034.

UCSC

uc002ruv.3. human.

Organism-specific databases

CTD

2034.

GeneCards

GC02P046436.

HGNC

HGNC:3374. EPAS1.

HPA

CAB012248.

MIM

603349. gene.
611783. phenotype.

neXtProt

NX_Q99814.

Orphanet

247511. Autosomal dominant secondary polycythemia.

PharmGKB

PA27809.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG289264.

HOGENOM

HOG000234306.

HOVERGEN

HBG060456.

InParanoid

Q99814.

KO

K09095.

OMA

QYQDYSL.

OrthoDB

EOG4XPQF6.

PhylomeDB

Q99814.

Enzyme and pathway databases

Pathway_Interaction_DB

vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.

Reactome

REACT_120956. Cellular responses to stress.

Gene expression databases

ArrayExpress

Q99814.

Bgee

Q99814.

CleanEx

HS_EPAS1.

Genevestigator

Q99814.

GermOnline

ENSG00000116016. Homo sapiens.

Family and domain databases

InterPro

IPR011598. 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]

Pfam

PF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]

PRINTS

PR00785. NCTRNSLOCATR.

SMART

SM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]

SUPFAM

SSF47459. HLH_basic. 1 hit.

TIGRFAMs

TIGR00229. sensory_box. 2 hits.

PROSITE

PS50888. BHLH. 1 hit.
PS50113. PAC. False negative.
PS50112. PAS. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q99814.

ChEMBL

CHEMBL1744522.

ChiTaRS

EPAS1. human.

EvolutionaryTrace

Q99814.

GenomeRNAi

2034.

NextBio

8255.

SOURCE

Search...

Entry information

Entry name

EPAS1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 142 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.