UniProtKB - Q9Y2N7 (HIF3A_HUMAN)
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Protein
Hypoxia-inducible factor 3-alpha
Gene
HIF3A
Organism
Homo sapiens (Human)
Status
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
- DNA binding Source: Ensembl
- protein dimerization activity Source: InterPro
- RNA polymerase II transcription factor activity, sequence-specific DNA binding Source: NTNU_SB
- transcription coactivator activity Source: UniProtKB
- transcription corepressor activity Source: UniProtKB
GO - Biological processi
- angiogenesis Source: UniProtKB-KW
- apoptotic process Source: UniProtKB-KW
- positive regulation of transcription by RNA polymerase II Source: GO_Central
- post-translational protein modification Source: Reactome
- protein ubiquitination Source: Reactome
- regulation of transcription by RNA polymerase II Source: UniProtKB
- regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: Reactome
- transcription by RNA polymerase II Source: Ensembl
Keywordsi
Molecular function | Developmental protein, Repressor |
Biological process | Angiogenesis, Apoptosis, Stress response, Transcription, Transcription regulation |
Enzyme and pathway databases
Reactomei | R-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 PublicationShort 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 | |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000124440.15. |
HGNCi | HGNC:15825. HIF3A. |
MIMi | 609976. gene. |
neXtProti | NX_Q9Y2N7. |
Pathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 467 | K → R: No loss of ubiquitination. Reduced ubiquitination; when associated with R-570. 1 Publication | 1 | |
Mutagenesisi | 492 | P → A: Reduced hydroxylation activity. Reduced ubiquitination. 1 Publication | 1 | |
Mutagenesisi | 570 | K → R: No loss of ubiquitination. Reduced ubiquitination; when associated with R-467. 1 Publication | 1 |
Keywords - Diseasei
Tumor suppressorOrganism-specific databases
DisGeNETi | 64344. |
OpenTargetsi | ENSG00000124440. |
PharmGKBi | PA29285. |
Polymorphism and mutation databases
BioMutai | HIF3A. |
DMDMi | 145558932. |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000284414 | 1 – 669 | Hypoxia-inducible factor 3-alphaAdd BLAST | 669 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Cross-linki | 467 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication | ||
Modified residuei | 492 | 4-hydroxyproline1 Publication | 1 | |
Cross-linki | 570 | Glycyl 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 conjugationProteomic databases
PaxDbi | Q9Y2N7. |
PeptideAtlasi | Q9Y2N7. |
PRIDEi | Q9Y2N7. |
PTM databases
iPTMneti | Q9Y2N7. |
PhosphoSitePlusi | Q9Y2N7. |
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
Bgeei | ENSG00000124440. |
CleanExi | HS_HIF3A. |
ExpressionAtlasi | Q9Y2N7. baseline and differential. |
Genevisiblei | Q9Y2N7. HS. |
Organism-specific databases
HPAi | HPA041141. |
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
- protein dimerization activity Source: InterPro
Protein-protein interaction databases
BioGridi | 122143. 3 interactors. |
ELMi | Q9Y2N7. |
STRINGi | 9606.ENSP00000366898. |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more detailsFeature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Beta strandi | 241 – 245 | Combined sources | 5 | |
Beta strandi | 250 – 254 | Combined sources | 5 | |
Helixi | 258 – 262 | Combined sources | 5 | |
Helixi | 266 – 269 | Combined sources | 4 | |
Helixi | 274 – 277 | Combined sources | 4 | |
Turni | 280 – 282 | Combined sources | 3 | |
Helixi | 283 – 296 | Combined sources | 14 | |
Beta strandi | 297 – 300 | Combined sources | 4 | |
Beta strandi | 304 – 307 | Combined sources | 4 | |
Beta strandi | 313 – 323 | Combined sources | 11 | |
Helixi | 329 – 331 | Combined sources | 3 | |
Beta strandi | 333 – 342 | Combined sources | 10 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
4WN5 | X-ray | 1.15 | A/B | 237-347 | [»] | |
ProteinModelPortali | Q9Y2N7. | |||||
SMRi | Q9Y2N7. | |||||
ModBasei | Search... | |||||
MobiDBi | Search... |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 14 – 67 | bHLHPROSITE-ProRule annotationAdd BLAST | 54 | |
Domaini | 82 – 154 | PAS 1PROSITE-ProRule annotationAdd BLAST | 73 | |
Domaini | 227 – 297 | PAS 2PROSITE-ProRule annotationAdd BLAST | 71 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 77 – 100 | Nuclear localization signalBy similarityAdd BLAST | 24 | |
Regioni | 230 – 274 | Nuclear export signalBy similarityAdd BLAST | 45 | |
Regioni | 452 – 581 | ODDAdd BLAST | 130 | |
Regioni | 454 – 506 | NTADAdd BLAST | 53 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 414 – 418 | LRRLL | 5 | |
Motifi | 490 – 497 | LAPYISMD | 8 |
Keywords - Domaini
RepeatPhylogenomic databases
eggNOGi | KOG3558. Eukaryota. ENOG410YK57. LUCA. |
GeneTreei | ENSGT00760000118788. |
HOGENOMi | HOG000234306. |
HOVERGENi | HBG060456. |
InParanoidi | Q9Y2N7. |
KOi | K09096. |
OMAi | PMAGARK. |
OrthoDBi | EOG091G0486. |
PhylomeDBi | Q9Y2N7. |
TreeFami | TF317772. |
Family and domain databases
CDDi | cd00083. HLH. 1 hit. cd00130. PAS. 2 hits. |
Gene3Di | 4.10.280.10. 1 hit. |
InterProi | View 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. |
Pfami | View protein in Pfam PF11413. HIF-1. 1 hit. PF00989. PAS. 1 hit. PF08447. PAS_3. 1 hit. |
SMARTi | View protein in SMART SM00353. HLH. 1 hit. SM00086. PAC. 1 hit. SM00091. PAS. 2 hits. |
SUPFAMi | SSF47459. SSF47459. 1 hit. SSF55785. SSF55785. 2 hits. |
TIGRFAMsi | TIGR00229. sensory_box. 1 hit. |
PROSITEi | View protein in PROSITE PS50888. BHLH. 1 hit. PS50112. PAS. 2 hits. |
s (7)i Sequence
Sequence statusi: Complete.
This entry describes 7 produced by isoformsialternative 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.
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
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 »Sequence cautioni
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 202 | A → V in BAB55324 (PubMed:14702039).Curated | 1 | |
Sequence conflicti | 497 | D → G in BAB55324 (PubMed:14702039).Curated | 1 |
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_031731 | 343 | Q → R1 PublicationCorresponds to variant dbSNP:rs3764609Ensembl. | 1 | |
Natural variantiVAR_031732 | 463 | F → L. Corresponds to variant dbSNP:rs7253301Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_043429 | 1 – 120 | MALGL…HLGLS → MRPAAGAARRPRCCTSWLTR CPSPAASAPTWTRPLSCASP SATCACTASAP in isoform 7. 1 PublicationAdd BLAST | 120 | |
Alternative sequenceiVSP_024518 | 1 – 86 | Missing in isoform 6. CuratedAdd BLAST | 86 | |
Alternative sequenceiVSP_024519 | 1 – 56 | Missing in isoform 5. 1 PublicationAdd BLAST | 56 | |
Alternative sequenceiVSP_024520 | 1 – 8 | MALGLQRA → MDWQDH in isoform 2. 1 Publication | 8 | |
Alternative sequenceiVSP_024521 | 87 – 137 | ACYLK…IHPCD → MRPAAGAARRPRCCTSWLTR CPSPAASAPTWTRPLSCASP SATCACTASAP in isoform 6. CuratedAdd BLAST | 51 | |
Alternative sequenceiVSP_024523 | 293 – 363 | LLSKG…HSRRP → CMYPISPGAKPAATWPPADT RTPQLPIPQDALPPHLNTSS LLPKPQGTVSFLAPSYPVPR SFSPHLPPWWP in isoform 4. 1 PublicationAdd BLAST | 71 | |
Alternative sequenceiVSP_024525 | 364 – 669 | Missing in isoform 4. 1 PublicationAdd BLAST | 306 | |
Alternative sequenceiVSP_024526 | 611 – 669 | SFLLT…SAQAD → VCWGINGILWPSLPSWLKPT VL in isoform 3. 3 PublicationsAdd BLAST | 59 |
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. |
CCDSi | CCDS12681.2. [Q9Y2N7-1] CCDS12682.1. [Q9Y2N7-2] CCDS42580.2. [Q9Y2N7-7] |
PIRi | JC7771. |
RefSeqi | NP_071907.4. NM_022462.4. [Q9Y2N7-7] NP_690007.1. NM_152794.3. [Q9Y2N7-2] NP_690008.2. NM_152795.3. [Q9Y2N7-1] |
UniGenei | Hs.420830. |
Genome annotation databases
Ensembli | ENST00000244303; ENSP00000244303; ENSG00000124440. [Q9Y2N7-7] ENST00000300862; ENSP00000300862; ENSG00000124440. [Q9Y2N7-2] ENST00000377670; ENSP00000366898; ENSG00000124440. [Q9Y2N7-1] |
GeneIDi | 64344. |
KEGGi | hsa:64344. |
UCSCi | uc002peh.3. human. [Q9Y2N7-1] |
Keywords - Coding sequence diversityi
Alternative splicing, PolymorphismSimilar proteinsi
Entry informationi
Entry namei | HIF3A_HUMAN | |
Accessioni | Q9Y2N7Primary (citable) accession number: Q9Y2N7 Secondary accession number(s): B0M185 Q9HAI2 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | April 17, 2007 |
Last sequence update: | April 17, 2007 | |
Last modified: | March 28, 2018 | |
This is version 145 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | 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. |