P97481 (EPAS1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Endothelial PAS domain-containing protein 1
Short name=EPAS-1

Alternative name(s):
HIF-1-alpha-like factor
Short name=HLF
Short name=mHLF
HIF-related factor
Short name=HRF
Hypoxia-inducible factor 2-alpha
Short name=HIF-2-alpha
Short name=HIF2-alpha

Gene names

Name:	Epas1
Synonyms:	Hif2a

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	874 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 requires recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD By similarity.
Subunit structure	Efficient DNA binding requires dimerization with another bHLH protein. Heterodimerizes with ARNT. Interacts with CREBPB. Ref.5
Subcellular location	Nucleus Potential.
Tissue specificity	Expressed in most tissues, with highest levels in lung, followed by heart, kidney, brain and liver. Predominantly expressed in endothelial cells. Also found in smooth muscle cells of the uterus, neurons, and brown adipose tissue. High expression in embryonic choroid plexus and kidney glomeruli.
Developmental stage	In day 11 embryo, expression is almost exclusively seen in endothelial cells of the intersegmental blood vessels separating the somites, the atrial and ventricular chambers of the heart, and the dorsal aorta. High expression also occurs in extraembryonic membranes. In the developing brain of day 13 embryo, endothelial cells of the highly vascularized choroid plexus contain high levels of EPAS1.
Post-translational modification	In normoxia, is probably hydroxylated on Pro-405 and Pro-530 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-851 by HIF1AN thus probably abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. Phosphorylated on multiple sites in the CTAD. Ref.5 The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.
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
Domain	Repeat
Ligand	DNA-binding
Molecular function	Activator Developmental protein
PTM	Hydroxylation Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from mutant phenotype PubMed 12053176PubMed 15728559PubMed 15851592. Source: MGI blood vessel remodeling Inferred from mutant phenotype PubMed 10880563. Source: MGI cell maturation Inferred from mutant phenotype PubMed 12053176. Source: MGI embryonic placenta development Inferred from genetic interaction PubMed 16287860. Source: MGI erythrocyte differentiation Inferred from mutant phenotype PubMed 17284606. Source: MGI lung development Inferred from mutant phenotype PubMed 12053176. Source: MGI mitochondrion organization Inferred from mutant phenotype PubMed 14608355. Source: MGI myoblast cell fate commitment Inferred from mutant phenotype PubMed 21106753. Source: BHF-UCL norepinephrine metabolic process Inferred from mutant phenotype PubMed 9808618. Source: MGI regulation of heart rate Inferred from mutant phenotype PubMed 9808618. Source: MGI regulation of transcription from RNA polymerase II promoter in response to oxidative stress Inferred from direct assay PubMed 14608355. Source: MGI response to hypoxia Inferred from mutant phenotype PubMed 15626745. Source: MGI surfactant homeostasis Inferred from mutant phenotype PubMed 12053176. Source: MGI visual perception Inferred from mutant phenotype PubMed 15728559. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay PubMed 12832481. Source: MGI transcription factor complex Inferred from direct assay PubMed 12464608. Source: MGI
Molecular_function	DNA binding Inferred from direct assay PubMed 12464608PubMed 17404621. Source: MGI RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Inferred from direct assay PubMed 21856340. Source: MGI histone acetyltransferase binding Inferred from sequence or structural similarity. Source: UniProtKB signal transducer activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 874	874	Endothelial PAS domain-containing protein 1		PRO_0000127420
Regions
	Domain	14 – 67	54	bHLH
	Domain	84 – 154	71	PAS 1
	Domain	230 – 300	71	PAS 2
	Domain	304 – 347	44	PAC
	Region	495 – 541	47	NTAD
	Region	834 – 874	41	CTAD
	Compositional bias	471 – 479	9	Poly-Ser
Amino acid modifications
	Modified residue	405	1	4-hydroxyproline By similarity
	Modified residue	530	1	4-hydroxyproline By similarity
	Modified residue	844	1	Phosphothreonine Ref.5
	Modified residue	851	1	(3S)-3-hydroxyasparagine Ref.6
Experimental info
	Mutagenesis	530	1	P → A: Confers transcriptional activity at normoxia; when associated with A-851. Ref.4
	Mutagenesis	844	1	T → A: Decreases interaction with CREBBP. Ref.5
	Mutagenesis	851	1	N → A: Confers transcriptional activity at normoxia; when associated with A-530. Ref.4
	Sequence conflict	25	1	C → S in BAA20130. Ref.2
	Sequence conflict	191	1	K → KS in AAB41496. Ref.1
	Sequence conflict	439 – 440	2	VS → AA in AAC12871. Ref.3
	Sequence conflict	463	1	D → G in AAC12871. Ref.3
	Sequence conflict	654	1	G → V in BAA20130. Ref.2
	Sequence conflict	663	1	A → P in BAA20130. Ref.2
	Sequence conflict	669	1	S → W in AAB41496. Ref.1
	Sequence conflict	673	1	P → L in AAB41496. Ref.1
	Sequence conflict	678	1	P → L in AAB41496. Ref.1
	Sequence conflict	725	1	D → E in AAC12871. Ref.3
	Sequence conflict	731	1	P → L in AAC12871. Ref.3
	Sequence conflict	762	1	A → G in AAC12871. Ref.3
	Sequence conflict	786	1	P → L in AAC12871. Ref.3
	Sequence conflict	791	1	S → F in AAC12871. Ref.3
	Sequence conflict	794	1	S → N in AAC12871. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	P97481 [UniParc]. Last modified December 15, 1998. Version 2. Checksum: A6FFA490AE43640C	FASTA	874	96,712
	10 20 30 40 50 60 MTADKEKKRS SSELRKEKSR DAARCRRSKE TEVFYELAHE LPLPHSVSSH LDKASIMRLA 70 80 90 100 110 120 ISFLRTHKLL SSVCSENESE AEADQQMDNL YLKALEGFIA VVTQDGDMIF LSENISKFMG 130 140 150 160 170 180 LTQVELTGHS IFDFTHPCDH EEIRENLTLK NGSGFGKKSK DVSTERDFFM RMKCTVTNRG 190 200 210 220 230 240 RTVNLKSATW KVLHCTGQVR VYNNCPPHSS LCGSKEPLLS CLIIMCEPIQ HPSHMDIPLD 250 260 270 280 290 300 SKTFLSRHSM DMKFTYCDDR ILELIGYHPE ELLGRSAYEF YHALDSENMT KSHQNLCTKG 310 320 330 340 350 360 QVVSGQYRML AKHGGYVWLE TQGTVIYNPR NLQPQCIMCV NYVLSEIEKN DVVFSMDQTE 370 380 390 400 410 420 SLFKPHLMAM NSIFDSSDDV AVTEKSNYLF TKLKEEPEEL AQLAPTPGDA IISLDFGSQN 430 440 450 460 470 480 FDEPSAYGKA ILPPGQPWVS GLRSHSAQSE SGSLPAFTVP QADTPGNTTP SASSSSSCST 490 500 510 520 530 540 PSSPEDYYSS LENPLKIEVI EKLFAMDTEP RDPGSTQTDF SELDLETLAP YIPMDGEDFQ 550 560 570 580 590 600 LSPICPEEPL MPESPQPTPQ HCFSTMTSIF QPLTPGATHG PFFLDKYPQQ LESRKTESEH 610 620 630 640 650 660 WPMSSIFFDA GSKGSLSPCC GQASTPLSSM GGRSNTQWPP DPPLHFGPTK WPVGDQSAES 670 680 690 700 710 720 LGALPVGSSQ LEPPSAPPHV SMFKMRSAKD FGARGPYMMS PAMIALSNKL KLKRQLEYEE 730 740 750 760 770 780 QAFQDTSGGD PPGTSSSHLM WKRMKSLMGG TCPLMPDKTI SANMAPDEFT QKSMRGLGQP 790 800 810 820 830 840 LRHLPPPQPP STRSSGENAK TGFPPQCYAS QFQDYGPPGA QKVSGVASRL LGPSFEPYLL 850 860 870 PELTRYDCEV NVPVPGSSTL LQGRDLLRAL DQAT

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]. Tissue: Brain.
[2]	"A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development." Ema M., Taya S., Yokotani N., Sogawa K., Matsuda Y., Fujii-Kuriyama Y. Proc. Natl. Acad. Sci. U.S.A. 94:4273-4278(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: C57BL/6. Tissue: Hypothalamus and Skeletal muscle.
[3]	"HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels." Flamme I., Froehlich T., von Reutern M., Kappel A., Damert A., Risau W. Mech. Dev. 63:51-60(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain capillary.
[4]	"FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor." Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K. Genes Dev. 16:1466-1471(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 846-864, MUTAGENESIS OF PRO-530 AND ASN-851.
[5]	"The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine." Gradin K., Takasaki C., Fujii-Kuriyama Y., Sogawa K. J. Biol. Chem. 277:23508-23514(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CREBBP, PHOSPHORYLATION AT THR-844, MUTAGENESIS OF THR-844.
[6]	"Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch." Lando D., Peet D.J., Whelan D.A., Gorman J.J., Whitelaw M.L. Science 295:858-861(2002) [PubMed] [Europe PMC] [Abstract] Cited for: HYDROXYLATION AT ASN-851.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U81983 mRNA. Translation: AAB41496.1. D89787 mRNA. Translation: BAA20130.1. AF045160 mRNA. Translation: AAC12871.1.
IPI	IPI00312615.
RefSeq	NP_034267.3. NM_010137.3.
UniGene	Mm.1415.
3D structure databases
ProteinModelPortal	P97481.
SMR	P97481. Positions 16-348, 840-872.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-46109N.
STRING	10090.ENSMUSP00000107892.
PTM databases
PhosphoSite	P97481.
Proteomic databases
PaxDb	P97481.
PRIDE	P97481.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000024954; ENSMUSP00000024954; ENSMUSG00000024140.
GeneID	13819.
KEGG	mmu:13819.
UCSC	uc008duj.2. mouse.
Organism-specific databases
CTD	2034.
MGI	MGI:109169. Epas1.
Phylogenomic databases
eggNOG	NOG289264.
GeneTree	ENSGT00650000093281.
HOGENOM	HOG000234306.
HOVERGEN	HBG060456.
InParanoid	P97481.
KO	K09095.
OMA	QYQDYSL.
OrthoDB	EOG4XPQF6.
Gene expression databases
Bgee	P97481.
CleanEx	MM_EPAS1.
Genevestigator	P97481.
GermOnline	ENSMUSG00000024140. Mus musculus.
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
ChiTaRS	EPAS1. mouse.
NextBio	284608.
SOURCE	Search...

Entry information

Entry name

EPAS1_MOUSE

Accession

Primary (citable) accession number: P97481
Secondary accession number(s): O08787, O55046

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 15, 1998
Last sequence update:	December 15, 1998
Last modified:	May 1, 2013
This is version 125 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program