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Protein

Hypoxia-inducible factor 3-alpha

Gene

Hif3a

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression (PubMed:9840812, PubMed:11734856, PubMed:21546903). Plays a role in the development of the cardiorespiratory system (PubMed:18070924).4 Publications
Isoform 1: Acts as positive regulator of hypoxia-inducible gene expression. Associates to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters in a ARNT-dependent manner, and hence also participates in the transcriptional activation of reporter genes driven by HRE (PubMed:9840812).1 Publication
Isoform 2: Attenuates the ability of transcription factor HIF1A, EPAS1 and the HIF1A-ARNT complex to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. May act as a tumor suppressor (PubMed:11734856). May also be involved in apoptosis (PubMed:21546903).2 Publications
Isoform 3: Attenuates the ability of transcription factor HIF1A, EPAS1 and the HIF1A-ARNT complex to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation (PubMed:18070924). Plays also a role in the development of the lung and heart during embryonic and neonatal stages (PubMed:18070924).1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Repressor

Keywords - Biological processi

Angiogenesis, Apoptosis, Stress response, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-MMU-1234158. Regulation of gene expression by Hypoxia-inducible Factor.
R-MMU-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

Names & Taxonomyi

Protein namesi
Recommended name:
Hypoxia-inducible factor 3-alpha1 Publication
Short name:
HIF-3-alpha
Short name:
HIF3-alpha
Alternative name(s):
Basic-helix-loop-helix-PAS protein MOP7
HIF3-alpha-1
Inhibitory PAS domain protein1 Publication
Short name:
IPAS1 Publication
Member of PAS protein 7
Neonatal and embryonic PAS protein1 Publication
Gene namesi
Name:Hif3aImported
Synonyms:Mop71 Publication, Nepas1 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 7

Organism-specific databases

MGIiMGI:1859778. Hif3a.

Subcellular locationi

  • Nucleus By similarity
  • Cytoplasm By similarity

  • Note: In the nuclei of all periportal and perivenous hepatocytes. In the distal perivenous zone, detected in the cytoplasm of the hepatocytes. Localized in the cytoplasm and nuclei under normoxia, but increased in the nucleus under hypoxic conditions. Colocalized with HIF1A in kidney tumors.By similarity
Isoform 2 :

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • mitochondrion Source: UniProtKB
  • nuclear speck Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice appeared outwardly normal and are viable and fertile. Show hypertrophy of the right atrium and ventricle, disarrangement of striated muscle fibers in the heart, and pulmonary hyperplasia (PubMed:18070924).1 Publication

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002844151 – 662Hypoxia-inducible factor 3-alphaAdd BLAST662

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki463Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei4874-hydroxyprolineBy similarity1
Cross-linki565Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity

Post-translational modificationi

In normoxia, hydroxylated on Pro-487 in the oxygen-dependent degradation domain (ODD) by PHD. The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation (By similarity).By similarity
Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.By similarity

Keywords - PTMi

Hydroxylation, Isopeptide bond, Ubl conjugation

Proteomic databases

EPDiQ0VBL6.
PaxDbiQ0VBL6.
PRIDEiQ0VBL6.

PTM databases

iPTMnetiQ0VBL6.
PhosphoSitePlusiQ0VBL6.

Expressioni

Tissue specificityi

Isoform 3 is expressed in endothelial cells of vessels and capillaries in alveoli of the neonatal lung (at protein level) (PubMed:18070924). Expressed in lung, brain, heart and kidney (PubMed:9840812). Isoform 2 is expressed in heart and lung (PubMed:12119283). Isoform 2 is highly expressed in the epithelial cell layer of the cornea with lower expression in the layers of ganglion cells, inner nuclear cells, and rods and cones of the retina (PubMed:11734856). Isoform 2 is expressed in the cerebellum only in the Purkinje cell layer (PubMed:11734856).4 Publications

Developmental stagei

Isoform 3 is expressed in brain, heart, lung, liver and kidney at 15.5 dpc. Isoform 3 is expressed in heart, lung, liver and kidney at 18.5 dpc.1 Publication

Inductioni

Isoform 2 is up-regulated in corneal epithelium cells under hypoxia (at protein level) (PubMed:11734856). Isoform 2 is up-regulated by hypoxia in a HIF1A-dependent manner (PubMed:12119283, PubMed:17355974). Isoform 3 is up-regulated by hypoxia (PubMed:18070924).4 Publications

Gene expression databases

BgeeiENSMUSG00000004328.
CleanExiMM_HIF3A.
ExpressionAtlasiQ0VBL6. baseline and differential.
GenevisibleiQ0VBL6. MM.

Interactioni

Subunit structurei

Isoform 1 interacts with ARNT (PubMed:9840812). Isoform 2 interacts with HIF1A (PubMed:11734856, PubMed:21546903). Isoform 2 interacts EPAS1 (PubMed:21546903). Isoform 2 interacts (via C-terminus domain) with BAD; the interaction reduces the binding between BAD and BAX (PubMed:21546903). Isoform 2 (via C-terminus domain) interacts with BCL2L2 and MCL1 (PubMed:21546903). Interacts with VHL (By similarity).By similarity3 Publications

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000104132.

Structurei

3D structure databases

ProteinModelPortaliQ0VBL6.
SMRiQ0VBL6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini12 – 65bHLHPROSITE-ProRule annotationAdd BLAST54
Domaini80 – 150PAS 1PROSITE-ProRule annotationAdd BLAST71
Domaini225 – 295PAS 2PROSITE-ProRule annotationAdd BLAST71

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni75 – 98Nuclear localization signal (isoform 2)1 PublicationAdd BLAST24
Regioni228 – 272Nuclear export signal (isoform 2)1 PublicationAdd BLAST45
Regioni448 – 581ODDAdd BLAST134
Regioni450 – 501NTADAdd BLAST52

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi414 – 418LRRLL5
Motifi485 – 492LAPYISMD8

Domaini

Isoform 2 contains a nuclear localization signal between amino acid positions 75 and 98. Isoform 2 contains a nuclear export signal between amino acid positions 228 and 272.1 Publication

Sequence similaritiesi

Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
Contains 2 PAS (PER-ARNT-SIM) domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3558. Eukaryota.
ENOG410YK57. LUCA.
GeneTreeiENSGT00760000118788.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiQ0VBL6.
KOiK09096.
OMAiPMAGARK.
OrthoDBiEOG091G0486.

Family and domain databases

InterProiIPR011598. bHLH_dom.
IPR021537. HIF_alpha_subunit.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]
SMARTiSM00353. HLH. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsiTIGR00229. sensory_box. 1 hit.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q0VBL6-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MDWDQDRSNT ELRKEKSRDA ARSRRSQETE VLYQLAHTLP FARGVSAHLD
60 70 80 90 100
KASIMRLTIS YLRMHRLCAA GEWNQVEKGG EPLDACYLKA LEGFVMVLTA
110 120 130 140 150
EGDMAYLSEN VSKHLGLSQL ELIGHSIFDF IHPCDQEELQ DALTPRPNLS
160 170 180 190 200
KKKLEAPTER HFSLRMKSTL TSRGRTLNLK AATWKVLHCS GHMRAYKPPA
210 220 230 240 250
QTSPAGSPRS EPPLQCLVLI CEAIPHPASL EPPLGRGAFL SRHSLDMKFT
260 270 280 290 300
YCDERIAEVA GYSPDDLIGC SAYEYIHALD SDAVSRSIHT LLSKGQAVTG
310 320 330 340 350
QYRFLARTGG YLWTQTQATV VSGGRGPQSE SIICVHFLIS RVEETGVVLS
360 370 380 390 400
LEQTEQHTRR PPRLSASSQK GIPGNSVDSP APRILAFLHP PALSEASLAA
410 420 430 440 450
DPRRFCSPDL RRLMAPILDG PPPAATPSTP QATRRPQSPL PADLPDKLTV
460 470 480 490 500
GLENAHRLST AQKNKTVETD LDIAQDPDTL DLEMLAPYIS MDDDFQLNSS
510 520 530 540 550
EQLPKVHRRP PRVARRPRAR SFHGLSPPIP EPSLLPRWGS DPRLNCSSPS
560 570 580 590 600
RGDRPTASLM PGTRKRALAQ SSEDKGLELL ETKPPKRSPR LEPGSFLLPP
610 620 630 640 650
LSLSFLLQGR QLPGNQQDPR APLVHSHEPL GLAPSLLSLC QHEETVQPRN
660
RFPPAAGLGQ TH
Length:662
Mass (Da):73,044
Last modified:July 27, 2011 - v2
Checksum:iD05E2B9CB2B63E4E
GO
Isoform 2 (identifier: Q0VBL6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-6: MDWDQD → MALGLQRV
     72-119: EWNQVEKGGE...NVSKHLGLSQ → GKRGRATGRL...HNPTPGTNFS
     226-291: HPASLEPPLG...DAVSRSIHTL → QLPFHDGATL...WALNRKNCPG
     292-662: Missing.

Note: Mutagenesis of Lys-75, Arg-76, Arg-97 and Arg-98 increase strongly cytoplasmic localization. Mutagenesis of Pro-228, Pro-229, Leu-271 and Leu-272 increase strongly nuclear localization.1 Publication
Show »
Length:307
Mass (Da):33,990
Checksum:iD89D3B225C9C3967
GO
Isoform 3 (identifier: Q0VBL6-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-6: MDWDQD → MALGLQRV

Show »
Length:664
Mass (Da):73,122
Checksum:iE47A38649E415D63
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti345T → N in BAE25907 (PubMed:16141072).Curated1
Sequence conflicti449T → A in AAC72734 (PubMed:9840812).Curated1
Sequence conflicti449T → A in AAF21782 (PubMed:9840812).Curated1
Sequence conflicti449T → A in AAI20588 (PubMed:15489334).Curated1
Sequence conflicti449T → A in BAF44519 (PubMed:18070924).Curated1
Sequence conflicti477P → S in AAC72734 (PubMed:9840812).Curated1
Sequence conflicti477P → S in AAF21782 (PubMed:9840812).Curated1
Sequence conflicti477P → S in AAI20588 (PubMed:15489334).Curated1
Sequence conflicti477P → S in BAF44519 (PubMed:18070924).Curated1
Sequence conflicti484M → I in BAE25907 (PubMed:16141072).Curated1
Sequence conflicti582T → I in AAC72734 (PubMed:9840812).Curated1
Sequence conflicti582T → I in AAF21782 (PubMed:9840812).Curated1
Sequence conflicti613P → L in AAC72734 (PubMed:9840812).Curated1
Sequence conflicti613P → L in AAF21782 (PubMed:9840812).Curated1
Sequence conflicti613P → L in AAI20588 (PubMed:15489334).Curated1
Sequence conflicti613P → L in BAF44519 (PubMed:18070924).Curated1
Sequence conflicti651R → H in AAC72734 (PubMed:9840812).Curated1
Sequence conflicti651R → H in BAF44519 (PubMed:18070924).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0245281 – 6MDWDQD → MALGLQRV in isoform 2 and isoform 3. 2 Publications6
Alternative sequenceiVSP_02452972 – 119EWNQV…LGLSQ → GKRGRATGRLLPEGPGGFRH GTHRRGRHGLPVGKCQQAPG PQSVDLCSSSLIHNPTPGTN FS in isoform 2. 1 PublicationAdd BLAST48
Alternative sequenceiVSP_024530226 – 291HPASL…SIHTL → QLPFHDGATLGLPQEKTPIS TLFTPLWKALLCLVKRWPVQ VLQGKGTESSLPSWVLWALN RKNCPG in isoform 2. 1 PublicationAdd BLAST66
Alternative sequenceiVSP_024531292 – 662Missing in isoform 2. 1 PublicationAdd BLAST371

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF060194 mRNA. Translation: AAC72734.1.
AH008971 Genomic DNA. Translation: AAF21782.1.
AF416641 mRNA. Translation: AAL39015.1.
AB289606 mRNA. Translation: BAF44519.1.
AC148976 Genomic DNA. No translation available.
BC120587 mRNA. Translation: AAI20588.1.
AK144472 mRNA. Translation: BAE25907.1.
CCDSiCCDS20860.1. [Q0VBL6-1]
CCDS52045.1. [Q0VBL6-3]
RefSeqiNP_001156422.1. NM_001162950.1. [Q0VBL6-3]
NP_058564.2. NM_016868.3. [Q0VBL6-1]
UniGeneiMm.135110.

Genome annotation databases

EnsembliENSMUST00000037762; ENSMUSP00000048248; ENSMUSG00000004328. [Q0VBL6-1]
ENSMUST00000108492; ENSMUSP00000104132; ENSMUSG00000004328. [Q0VBL6-3]
GeneIDi53417.
KEGGimmu:53417.
UCSCiuc009fir.2. mouse. [Q0VBL6-1]
uc009fit.2. mouse. [Q0VBL6-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF060194 mRNA. Translation: AAC72734.1.
AH008971 Genomic DNA. Translation: AAF21782.1.
AF416641 mRNA. Translation: AAL39015.1.
AB289606 mRNA. Translation: BAF44519.1.
AC148976 Genomic DNA. No translation available.
BC120587 mRNA. Translation: AAI20588.1.
AK144472 mRNA. Translation: BAE25907.1.
CCDSiCCDS20860.1. [Q0VBL6-1]
CCDS52045.1. [Q0VBL6-3]
RefSeqiNP_001156422.1. NM_001162950.1. [Q0VBL6-3]
NP_058564.2. NM_016868.3. [Q0VBL6-1]
UniGeneiMm.135110.

3D structure databases

ProteinModelPortaliQ0VBL6.
SMRiQ0VBL6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000104132.

PTM databases

iPTMnetiQ0VBL6.
PhosphoSitePlusiQ0VBL6.

Proteomic databases

EPDiQ0VBL6.
PaxDbiQ0VBL6.
PRIDEiQ0VBL6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000037762; ENSMUSP00000048248; ENSMUSG00000004328. [Q0VBL6-1]
ENSMUST00000108492; ENSMUSP00000104132; ENSMUSG00000004328. [Q0VBL6-3]
GeneIDi53417.
KEGGimmu:53417.
UCSCiuc009fir.2. mouse. [Q0VBL6-1]
uc009fit.2. mouse. [Q0VBL6-2]

Organism-specific databases

CTDi64344.
MGIiMGI:1859778. Hif3a.

Phylogenomic databases

eggNOGiKOG3558. Eukaryota.
ENOG410YK57. LUCA.
GeneTreeiENSGT00760000118788.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiQ0VBL6.
KOiK09096.
OMAiPMAGARK.
OrthoDBiEOG091G0486.

Enzyme and pathway databases

ReactomeiR-MMU-1234158. Regulation of gene expression by Hypoxia-inducible Factor.
R-MMU-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

Miscellaneous databases

PROiQ0VBL6.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000004328.
CleanExiMM_HIF3A.
ExpressionAtlasiQ0VBL6. baseline and differential.
GenevisibleiQ0VBL6. MM.

Family and domain databases

InterProiIPR011598. bHLH_dom.
IPR021537. HIF_alpha_subunit.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]
SMARTiSM00353. HLH. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsiTIGR00229. sensory_box. 1 hit.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHIF3A_MOUSE
AccessioniPrimary (citable) accession number: Q0VBL6
Secondary accession number(s): A1IM61
, E9QLB1, Q3UN40, Q8VHR1, Q9QX54, Q9Z2I5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 17, 2007
Last sequence update: July 27, 2011
Last modified: November 2, 2016
This is version 92 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.