Reviewed, UniProtKB/Swiss-Prot Q99814 (EPAS1_HUMAN)

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	870 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
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.
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.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation Transcription Transcription regulation
Cellular component	Nucleus
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
Gene Ontology (GO)
Biological process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription from RNA polymerase II promoter Ref.1 Inferred from genetic interaction. Source: MGI response to hypoxia Inferred from direct assay. Source: MGI signal transduction Ref.2 Traceable author statement. Source: ProtInc transcription from RNA polymerase II promoter Ref.2 Traceable author statement. Source: ProtInc
Cellular component	transcription factor complex Ref.1 Inferred from direct assay. Source: MGI
Molecular function	RNA polymerase II transcription factor activity, enhancer binding Ref.2 Traceable author statement. Source: ProtInc histone acetyltransferase binding Inferred from physical interaction. Source: UniProtKB protein heterodimerization activity Ref.2 Inferred from physical interaction. Source: UniProtKB signal transducer activity Inferred from electronic annotation. Source: InterPro transcription coactivator activity Ref.2 Traceable author statement. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARNTL2	Q8WYA1	2	EBI-447470,EBI-1793513
BBS4	Q96RK4	1	EBI-447470,EBI-1805814
EIF3E	P60228	7	EBI-447470,EBI-347740
EP300	Q09472	1	EBI-447470,EBI-447295
MAX	P61244	2	EBI-447470,EBI-878388

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

28 – 68

41

Helix-loop-helix motif

Domain

84 – 154

71

PAS 1

Domain

230 – 300

71

PAS 2

Domain

304 – 347

44

PAC

DNA binding

15 – 27

13

Basic motif

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

537

1

G → W in ECYT4; gain of function; affects hydroxylation. Ref.5

VAR_042443

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

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

870

Helix Strand Turn

Details...

Beta strand

242 – 248

7

Beta strand

255 – 257

3

Helix

261 – 264

4

Helix

269 – 272

4

Helix

277 – 279

3

Beta strand

283 – 285

3

Helix

286 – 296

11

Turn

297 – 299

3

Beta strand

300 – 310

11

Beta strand

316 – 327

12

Turn

329 – 331

3

Beta strand

333 – 348

16

Sequences

	Sequence		Length	Mass (Da)
	Q99814-1 [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: 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

EMBLGenBankDDBJ

U81984 mRNA. Translation: AAB41495.1.
U51626 mRNA. Translation: AAC51212.1.
BC051338 mRNA. Translation: AAH51338.1.

IPI

IPI00294084.

RefSeq

NP_001421.2.

UniGene

Hs.468410

3D structure databases

PDBPDBe

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	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q99814. 10 interactions.

PTM databases

PhosphoSite

Q99814.

Proteomic databases

PRIDE

Q99814.

Genome annotation databases

Ensembl

ENSG00000116016. Homo sapiens. [Contig view]

GeneID

2034.

KEGG

hsa:2034.

UCSC

uc002ruv.1. human.

Organism-specific databases

GeneCards

GC02P046436.

H-InvDB

HIX0002028.

HGNC

HGNC:3374. EPAS1.

HPA

CAB012248.

MIM

603349. gene.
611783. phenotype.

PharmGKB

PA27809.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q99814.

HOVERGEN

Q99814.

OMA

Q99814. IEKNDVV.

Enzyme and pathway databases

Pathway_Interaction_DB

vegfr1_2_pathway. Signaling events mediated by VEGFR1 and VEGFR2.

Gene expression databases

ArrayExpress

Q99814.

Bgee

Q99814.

CleanEx

HS_EPAS1.

GermOnline

ENSG00000116016. Homo sapiens.

Family and domain databases

InterPro

IPR014887. HIF-1_TAD_C.
IPR001092. HLH_basic.
IPR001067. Nuc_translocat.
IPR001610. PAC.
IPR000014. PAS.
IPR013655. PAS_fold_3.
[Graphical view]

Pfam

PF08778. HIF-1a_CTAD. 1 hit.
PF00010. HLH. 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]

PROSITE

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

ProtoNet

Search...

Other Resources

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:	July 7, 2009
This is version 104 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)