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UniProtKB - Q9Y2N7 (HIF3A_HUMAN)

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Protein

Hypoxia-inducible factor 3-alpha

Gene

HIF3A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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:11573933, PubMed:16126907, PubMed:19694616, PubMed:20416395, PubMed:21069422). Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis (By similarity).By similarity5 Publications
Isoform 2: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression.1 Publication
Isoform 3: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.3 Publications
isoform 4: Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A 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:16126907, PubMed:17998805, PubMed:19694616, PubMed:20416395). May act as a tumor suppressor and inhibits malignant cell transformation (PubMed:17998805).4 Publications
Isoform 5: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.1 Publication

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionDevelopmental protein, Repressor
Biological processAngiogenesis, Apoptosis, Stress response, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-1234158 Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-452723 Transcriptional regulation of pluripotent stem cells
R-HSA-8951664 Neddylation

Names & Taxonomyi

Protein namesi
Recommended name:
Hypoxia-inducible factor 3-alpha1 Publication
Short name:
HIF-3-alpha1 Publication
Short name:
HIF3-alpha
Alternative name(s):
Basic-helix-loop-helix-PAS protein MOP7
Class E basic helix-loop-helix protein 17
Short name:
bHLHe17
HIF3-alpha-1
Inhibitory PAS domain protein
Short name:
IPAS
Member of PAS protein 7
PAS domain-containing protein 7
Gene namesi
Name:HIF3AImported
Synonyms:BHLHE17, MOP7, PASD7
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000124440.15
HGNCiHGNC:15825 HIF3A
MIMi609976 gene
neXtProtiNX_Q9Y2N7

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi467K → R: No loss of ubiquitination. Reduced ubiquitination; when associated with R-570. 1 Publication1
Mutagenesisi492P → A: Reduced hydroxylation activity. Reduced ubiquitination. 1 Publication1
Mutagenesisi570K → R: No loss of ubiquitination. Reduced ubiquitination; when associated with R-467. 1 Publication1

Keywords - Diseasei

Tumor suppressor

Organism-specific databases

DisGeNETi64344
OpenTargetsiENSG00000124440
PharmGKBiPA29285

Polymorphism and mutation databases

BioMutaiHIF3A
DMDMi145558932

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002844141 – 669Hypoxia-inducible factor 3-alphaAdd BLAST669

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki467Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei4924-hydroxyproline1 Publication1
Cross-linki570Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication

Post-translational modificationi

In normoxia, hydroxylated on Pro-492 in the oxygen-dependent degradation domain (ODD) by prolyl hydroxylase(s) (PHD). The hydroxylated proline promotes interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation.1 Publication
Ubiquitinated; ubiquitination occurs in a VHL- and oxygen-dependent pathway and subsequently targeted for proteasomal degradation.1 Publication

Keywords - PTMi

Hydroxylation, Isopeptide bond, Ubl conjugation

Proteomic databases

PaxDbiQ9Y2N7
PeptideAtlasiQ9Y2N7
PRIDEiQ9Y2N7

PTM databases

iPTMnetiQ9Y2N7
PhosphoSitePlusiQ9Y2N7

Expressioni

Tissue specificityi

Expressed in vascular cells (at protein level) (PubMed:21069422). Expressed in kidney (PubMed:11573933, PubMed:19694616). Expressed in lung epithelial cells (PubMed:16775626). Expressed in endothelial cells (venous and arterial cells from umbilical cord and aortic endothelial cells) and in vascular smooth muscle cells (aorta) (PubMed:21069422). Strongly expressed in the heart, placenta, and skeletal muscle, whereas a weak expression profile was found in the lung, liver, and kidney (PubMed:12538644). Expressed weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal cells (PubMed:16126907). Expression is down-regulated in numerous kidney tumor cells compared to non tumor kidney tissues (PubMed:16126907). Isoform 2 is expressed in heart, placenta, lung, liver, skeletal muscle and pancreas and in numerous cancer cell lines (PubMed:20416395). Isoform 3 and isoform 4 are weakly expressed in heart, placenta, lung, liver, skeletal muscle and pancreas (PubMed:20416395). Isoform 4 is expressed in fetal tissues, such as heart, brain, thymus, lung, liver, skeletal kidney and spleen (PubMed:20416395). Isoform 3 is weakly expressed in fetal tissues, such as liver and kidney (PubMed:20416395).7 Publications

Inductioni

Up-regulated by hypoxia (at protein level) (PubMed:16775626). Induced by hypoxia (PubMed:16775626). Isoform 2, isoform 3, isoform 4 and isoform 5 are up-regulated by hypoxia in a HIF1A- and EPAS1/HIF2A-dependent manner (PubMed:19694616, PubMed:20416395, PubMed:21069422). Isoform 4 is down-regulated by hypoxia and up-regulated upon restoring normoxia in embryonic kidney cells (PubMed:16126907).5 Publications

Gene expression databases

BgeeiENSG00000124440
CleanExiHS_HIF3A
ExpressionAtlasiQ9Y2N7 baseline and differential
GenevisibleiQ9Y2N7 HS

Organism-specific databases

HPAiHPA041141

Interactioni

Subunit structurei

Isoform 2 interacts (via ODD domain) with VHL (via beta domain) (PubMed:12538644). Isoform 4 interacts with HIF1A; the interaction inhibits the binding of HIF1A to hypoxia-responsive element (HRE) and HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with ARNT; the interaction occurs in a HIF1A- and DNA-binding-independent manner and does not induce HIF1A/ARNT-dependent transcriptional activation (PubMed:16126907). Isoform 4 interacts with EPAS1 (PubMed:17998805). Interacts with BAD, BCL2L2 and MCL1 (By similarity).By similarity3 Publications

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi122143, 3 interactors
ELMiQ9Y2N7
STRINGi9606.ENSP00000366898

Structurei

Secondary structure

1669
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi241 – 245Combined sources5
Beta strandi250 – 254Combined sources5
Helixi258 – 262Combined sources5
Helixi266 – 269Combined sources4
Helixi274 – 277Combined sources4
Turni280 – 282Combined sources3
Helixi283 – 296Combined sources14
Beta strandi297 – 300Combined sources4
Beta strandi304 – 307Combined sources4
Beta strandi313 – 323Combined sources11
Helixi329 – 331Combined sources3
Beta strandi333 – 342Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4WN5X-ray1.15A/B237-347[»]
ProteinModelPortaliQ9Y2N7
SMRiQ9Y2N7
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini14 – 67bHLHPROSITE-ProRule annotationAdd BLAST54
Domaini82 – 154PAS 1PROSITE-ProRule annotationAdd BLAST73
Domaini227 – 297PAS 2PROSITE-ProRule annotationAdd BLAST71

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni77 – 100Nuclear localization signalBy similarityAdd BLAST24
Regioni230 – 274Nuclear export signalBy similarityAdd BLAST45
Regioni452 – 581ODDAdd BLAST130
Regioni454 – 506NTADAdd BLAST53

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi414 – 418LRRLL5
Motifi490 – 497LAPYISMD8

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3558 Eukaryota
ENOG410YK57 LUCA
GeneTreeiENSGT00760000118788
HOGENOMiHOG000234306
HOVERGENiHBG060456
InParanoidiQ9Y2N7
KOiK09096
OMAiPMAGARK
OrthoDBiEOG091G0486
PhylomeDBiQ9Y2N7
TreeFamiTF317772

Family and domain databases

CDDicd00083 HLH, 1 hit
cd00130 PAS, 2 hits
Gene3Di4.10.280.10, 1 hit
InterProiView protein in InterPro
IPR011598 bHLH_dom
IPR021537 HIF_alpha_subunit
IPR036638 HLH_DNA-bd_sf
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013767 PAS_fold
IPR013655 PAS_fold_3
PfamiView protein in Pfam
PF11413 HIF-1, 1 hit
PF00989 PAS, 1 hit
PF08447 PAS_3, 1 hit
SMARTiView protein in SMART
SM00353 HLH, 1 hit
SM00086 PAC, 1 hit
SM00091 PAS, 2 hits
SUPFAMiSSF47459 SSF47459, 1 hit
SSF55785 SSF55785, 2 hits
TIGRFAMsiTIGR00229 sensory_box, 1 hit
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

Sequences (7)i

Sequence statusi: Complete.

This entry describes 7 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.2 Publications
Isoform 1 (identifier: Q9Y2N7-1) [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
MALGLQRARS TTELRKEKSR DAARSRRSQE TEVLYQLAHT LPFARGVSAH 
        60         70         80         90        100
LDKASIMRLT ISYLRMHRLC AAGEWNQVGA GGEPLDACYL KALEGFVMVL 
       110        120        130        140        150
TAEGDMAYLS ENVSKHLGLS QLELIGHSIF DFIHPCDQEE LQDALTPQQT 
       160        170        180        190        200
LSRRKVEAPT ERCFSLRMKS TLTSRGRTLN LKAATWKVLN CSGHMRAYKP 
       210        220        230        240        250
PAQTSPAGSP DSEPPLQCLV LICEAIPHPG SLEPPLGRGA FLSRHSLDMK 
       260        270        280        290        300
FTYCDDRIAE VAGYSPDDLI GCSAYEYIHA LDSDAVSKSI HTLLSKGQAV 
       310        320        330        340        350
TGQYRFLARS GGYLWTQTQA TVVSGGRGPQ SESIVCVHFL ISQVEETGVV 
       360        370        380        390        400
LSLEQTEQHS RRPIQRGAPS QKDTPNPGDS LDTPGPRILA FLHPPSLSEA 
       410        420        430        440        450
ALAADPRRFC SPDLRRLLGP ILDGASVAAT PSTPLATRHP QSPLSADLPD 
       460        470        480        490        500
ELPVGTENVH RLFTSGKDTE AVETDLDIAQ DADALDLEML APYISMDDDF 
       510        520        530        540        550
QLNASEQLPR AYHRPLGAVP RPRARSFHGL SPPALEPSLL PRWGSDPRLS 
       560        570        580        590        600
CSSPSRGDPS ASSPMAGARK RTLAQSSEDE DEGVELLGVR PPKRSPSPEH 
       610        620        630        640        650
ENFLLFPLSL SFLLTGGPAP GSLQDPSTPL LNLNEPLGLG PSLLSPYSDE 
       660 
DTTQPGGPFQ PRAGSAQAD
Length:669
Mass (Da):72,433
Last modified:April 17, 2007 - v2
Checksum:i81C4C84517000DE2
GO
Isoform 2 (identifier: Q9Y2N7-2) [UniParc]FASTAAdd to basket
Also known as: HIF-3alpha11 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     1-8: MALGLQRA → MDWQDH

Show »
Length:667
Mass (Da):72,405
Checksum:i67B8794FF9DCCF4B
GO
Isoform 3 (identifier: Q9Y2N7-3) [UniParc]FASTAAdd to basket
Also known as: HIF-3alpha21 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     611-669: SFLLTGGPAP...QPRAGSAQAD → VCWGINGILWPSLPSWLKPTVL

Show »
Length:632
Mass (Da):68,964
Checksum:i9665B0AF3998F8EF
GO
Isoform 4 (identifier: Q9Y2N7-4) [UniParc]FASTAAdd to basket
Also known as: HIF-3alpha41 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     293-363: LLSKGQAVTG...EQTEQHSRRP → CMYPISPGAK...FSPHLPPWWP
     364-669: Missing.

Show »
Length:363
Mass (Da):39,962
Checksum:i66CE5B85A2C50A15
GO
Isoform 5 (identifier: Q9Y2N7-5) [UniParc]FASTAAdd to basket
Also known as: HIF-3alpha31 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     1-56: Missing.

Note: Incomplete sequence. No experimental confirmation available.
Show »
Length:613
Mass (Da):66,142
Checksum:i4F2122D0D17C55A6
GO
Isoform 6 (identifier: Q9Y2N7-6) [UniParc]FASTAAdd to basket
Also known as: HIF-3alpha61 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     1-86: Missing.
     87-137: ACYLKALEGF...SIFDFIHPCD → MRPAAGAARR...ATCACTASAP

Note: Incomplete sequence. No experimental confirmation available.
Show »
Length:583
Mass (Da):62,393
Checksum:i04D6B8408073EEB4
GO
Isoform 7 (identifier: Q9Y2N7-7) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-120: MALGLQRARS...ENVSKHLGLS → MRPAAGAARR...ATCACTASAP

Note: No experimental confirmation available.
Show »
Length:600
Mass (Da):64,359
Checksum:i822B55E0513AF129
GO

Sequence cautioni

The sequence AAL69947 differs from that shown. Intron retention.Curated
The sequence BAB13865 differs from that shown. Aberrant splicing site.Curated
The sequence BAB14824 differs from that shown. Unlikely isoform. Aberrant splice sites.Curated
The sequence BAB55324 differs from that shown. Intron retention.Curated
The sequence BAD93355 differs from that shown. Intron retention.Curated
The sequence BAG07185 differs from that shown. Intron retention.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti202A → V in BAB55324 (PubMed:14702039).Curated1
Sequence conflicti497D → G in BAB55324 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_031731343Q → R1 PublicationCorresponds to variant dbSNP:rs3764609Ensembl.1
Natural variantiVAR_031732463F → L. Corresponds to variant dbSNP:rs7253301Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0434291 – 120MALGL…HLGLS → MRPAAGAARRPRCCTSWLTR CPSPAASAPTWTRPLSCASP SATCACTASAP in isoform 7. 1 PublicationAdd BLAST120
Alternative sequenceiVSP_0245181 – 86Missing in isoform 6. CuratedAdd BLAST86
Alternative sequenceiVSP_0245191 – 56Missing in isoform 5. 1 PublicationAdd BLAST56
Alternative sequenceiVSP_0245201 – 8MALGLQRA → MDWQDH in isoform 2. 1 Publication8
Alternative sequenceiVSP_02452187 – 137ACYLK…IHPCD → MRPAAGAARRPRCCTSWLTR CPSPAASAPTWTRPLSCASP SATCACTASAP in isoform 6. CuratedAdd BLAST51
Alternative sequenceiVSP_024523293 – 363LLSKG…HSRRP → CMYPISPGAKPAATWPPADT RTPQLPIPQDALPPHLNTSS LLPKPQGTVSFLAPSYPVPR SFSPHLPPWWP in isoform 4. 1 PublicationAdd BLAST71
Alternative sequenceiVSP_024525364 – 669Missing in isoform 4. 1 PublicationAdd BLAST306
Alternative sequenceiVSP_024526611 – 669SFLLT…SAQAD → VCWGINGILWPSLPSWLKPT VL in isoform 3. 3 PublicationsAdd BLAST59

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB054067 mRNA Translation: BAB69689.1
AF463492 mRNA Translation: AAL69947.1 Sequence problems.
AB118749 mRNA Translation: BAD93355.1 Sequence problems.
AB295039 mRNA Translation: BAG07185.1 Sequence problems.
AK021653 mRNA Translation: BAB13865.1 Sequence problems.
AK024095 mRNA Translation: BAB14824.1 Sequence problems.
AK027725 mRNA Translation: BAB55324.1 Sequence problems.
AK297828 mRNA Translation: BAG60164.1
AC007193 Genomic DNA Translation: AAD22668.1
CH471126 Genomic DNA Translation: EAW57410.1
BC026308 mRNA Translation: AAH26308.1
BC080551 mRNA Translation: AAH80551.1
CCDSiCCDS12681.2 [Q9Y2N7-1]
CCDS12682.1 [Q9Y2N7-2]
CCDS42580.2 [Q9Y2N7-7]
PIRiJC7771
RefSeqiNP_071907.4, NM_022462.4 [Q9Y2N7-7]
NP_690007.1, NM_152794.3 [Q9Y2N7-2]
NP_690008.2, NM_152795.3 [Q9Y2N7-1]
UniGeneiHs.420830

Genome annotation databases

EnsembliENST00000244303; ENSP00000244303; ENSG00000124440 [Q9Y2N7-7]
ENST00000300862; ENSP00000300862; ENSG00000124440 [Q9Y2N7-2]
ENST00000377670; ENSP00000366898; ENSG00000124440 [Q9Y2N7-1]
GeneIDi64344
KEGGihsa:64344
UCSCiuc002peh.3 human [Q9Y2N7-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiHIF3A_HUMAN
AccessioniPrimary (citable) accession number: Q9Y2N7
Secondary accession number(s): B0M185
, B4DNA2, I6L988, Q58A43, Q66K72, Q8WXA1, Q96K34, Q9H7Z9, Q9HAI2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 17, 2007
Last sequence update: April 17, 2007
Last modified: May 23, 2018
This is version 146 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references

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