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Protein

Hypoxia-inducible factor 1-alpha

Gene

HIF1A

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia.10 Publications

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • histone acetyltransferase binding Source: UniProtKB
  • Hsp90 protein binding Source: BHF-UCL
  • nuclear hormone receptor binding Source: UniProtKB
  • protein heterodimerization activity Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • sequence-specific DNA binding Source: Ensembl
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding Source: Ensembl
  • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding Source: BHF-UCL
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding Source: BHF-UCL
  • transcription factor activity, RNA polymerase II transcription factor binding Source: Ensembl
  • transcription factor activity, sequence-specific DNA binding Source: UniProtKB
  • transcription factor activity, transcription factor binding Source: BHF-UCL
  • transcription factor binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

  • angiogenesis Source: Ensembl
  • axonal transport of mitochondrion Source: UniProtKB
  • B-1 B cell homeostasis Source: Ensembl
  • cardiac ventricle morphogenesis Source: Ensembl
  • cartilage development Source: Ensembl
  • cellular iron ion homeostasis Source: Ensembl
  • cellular response to hypoxia Source: UniProtKB
  • cellular response to interleukin-1 Source: BHF-UCL
  • cerebral cortex development Source: Ensembl
  • collagen metabolic process Source: BHF-UCL
  • connective tissue replacement involved in inflammatory response wound healing Source: BHF-UCL
  • digestive tract morphogenesis Source: Ensembl
  • dopaminergic neuron differentiation Source: Ensembl
  • elastin metabolic process Source: BHF-UCL
  • embryonic hemopoiesis Source: Ensembl
  • embryonic placenta development Source: Ensembl
  • epithelial cell differentiation involved in mammary gland alveolus development Source: Ensembl
  • epithelial to mesenchymal transition Source: BHF-UCL
  • glucose homeostasis Source: Ensembl
  • heart looping Source: Ensembl
  • hemoglobin biosynthetic process Source: Ensembl
  • hypoxia-inducible factor-1alpha signaling pathway Source: Ensembl
  • intestinal epithelial cell maturation Source: Ensembl
  • iris morphogenesis Source: Ensembl
  • lactate metabolic process Source: Ensembl
  • lactation Source: Ensembl
  • mRNA transcription from RNA polymerase II promoter Source: BHF-UCL
  • muscle cell cellular homeostasis Source: Ensembl
  • negative regulation of bone mineralization Source: Ensembl
  • negative regulation of growth Source: Ensembl
  • negative regulation of mesenchymal cell apoptotic process Source: Ensembl
  • negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway Source: ParkinsonsUK-UCL
  • negative regulation of reactive oxygen species metabolic process Source: Ensembl
  • negative regulation of thymocyte apoptotic process Source: Ensembl
  • negative regulation of TOR signaling Source: Ensembl
  • neural crest cell migration Source: Ensembl
  • neural fold elevation formation Source: Ensembl
  • outflow tract morphogenesis Source: Ensembl
  • oxygen homeostasis Source: HGNC
  • positive regulation of angiogenesis Source: UniProtKB
  • positive regulation of chemokine-mediated signaling pathway Source: BHF-UCL
  • positive regulation of chemokine production Source: BHF-UCL
  • positive regulation of endothelial cell proliferation Source: BHF-UCL
  • positive regulation of epithelial cell migration Source: BHF-UCL
  • positive regulation of erythrocyte differentiation Source: BHF-UCL
  • positive regulation of gene expression Source: BHF-UCL
  • positive regulation of glycolytic process Source: BHF-UCL
  • positive regulation of hormone biosynthetic process Source: BHF-UCL
  • positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
  • positive regulation of macroautophagy Source: Ensembl
  • positive regulation of mitophagy Source: Ensembl
  • positive regulation of neuroblast proliferation Source: Ensembl
  • positive regulation of nitric-oxide synthase activity Source: BHF-UCL
  • positive regulation of pri-miRNA transcription from RNA polymerase II promoter Source: BHF-UCL
  • positive regulation of receptor biosynthetic process Source: BHF-UCL
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: UniProtKB
  • positive regulation of vascular endothelial growth factor production Source: UniProtKB
  • positive regulation of vascular endothelial growth factor receptor signaling pathway Source: BHF-UCL
  • regulation of aerobic respiration Source: Ensembl
  • regulation of gene expression Source: UniProtKB
  • regulation of transcription, DNA-templated Source: UniProtKB
  • regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: Reactome
  • regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: BHF-UCL
  • regulation of transforming growth factor beta2 production Source: BHF-UCL
  • response to hypoxia Source: UniProtKB
  • response to muscle activity Source: Ensembl
  • retina vasculature development in camera-type eye Source: Ensembl
  • signal transduction Source: BHF-UCL
  • transcription from RNA polymerase II promoter Source: UniProtKB
  • vascular endothelial growth factor production Source: BHF-UCL
  • visual learning Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

Enzyme and pathway databases

BioCyciZFISH:ENSG00000100644-MONOMER.
ReactomeiR-HSA-1234158. Regulation of gene expression by Hypoxia-inducible Factor.
R-HSA-1234162. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
R-HSA-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
R-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-HSA-2122947. NOTCH1 Intracellular Domain Regulates Transcription.
R-HSA-400253. Circadian Clock.
R-HSA-5689880. Ub-specific processing proteases.
R-HSA-8849473. PTK6 Expression.
R-HSA-8857538. PTK6 promotes HIF1A stabilization.
SignaLinkiQ16665.
SIGNORiQ16665.

Names & Taxonomyi

Protein namesi
Recommended name:
Hypoxia-inducible factor 1-alpha
Short name:
HIF-1-alpha
Short name:
HIF1-alpha
Alternative name(s):
ARNT-interacting protein
Basic-helix-loop-helix-PAS protein MOP1
Class E basic helix-loop-helix protein 78
Short name:
bHLHe78
Member of PAS protein 1
PAS domain-containing protein 8
Gene namesi
Name:HIF1A
Synonyms:BHLHE78, MOP1, PASD8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

HGNCiHGNC:4910. HIF1A.

Subcellular locationi

GO - Cellular componenti

  • axon cytoplasm Source: GOC
  • cytoplasm Source: UniProtKB
  • cytosol Source: UniProtKB
  • motile cilium Source: Ensembl
  • nuclear speck Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB
  • RNA polymerase II transcription factor complex Source: BHF-UCL
  • transcription factor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi247S → A: Constitutive kinase activity. 1 Publication1
Mutagenesisi247S → D: Impaired kinase activity. 1 Publication1
Mutagenesisi377K → R: No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-391; R-477 and R-532. 1 Publication1
Mutagenesisi389K → R: No change in sumoylation. 1 Publication1
Mutagenesisi391K → R: Abolishes 1 sumoylation. Abolishes 1 sumoylation; when associated with R-532. Abolishes 2 sumoylations; when associated with R-477. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-477 and R-532. 2 Publications1
Mutagenesisi392K → R: No change in sumoylation. 1 Publication1
Mutagenesisi394P → A: No change in VHLE3-dependent ubiquitination. 1 Publication1
Mutagenesisi397L → A: Abolishes VHLE3-dependent ubiquitination; when associated with A-400. 1 Publication1
Mutagenesisi400L → A: Abolishes VHLE3-dependent ubiquitination; when associated with A-397. 1 Publication1
Mutagenesisi402P → A: Abolishes in VHLE3-dependent ubiquitination, abolishes oxygen-dependent regulation of VP16, partially reduced VHLE target site ubiquitination and no interaction with VHL. No VHLE target site ubiquitination; when associated with G-564. Increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation; when associated with A-564. 3 Publications1
Mutagenesisi442K → R: No change in sumoylation. 1 Publication1
Mutagenesisi460K → R: No change in sumoylation nor in ARD1-mediated acetylation. 1 Publication1
Mutagenesisi477K → R: Abolishes 1 sumoylation. Abolishes 2 sumoylations; when associated with R-391. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-532. 2 Publications1
Mutagenesisi532K → R: Reduced ubiquitination. No change in sumoylation nor on interaction with ARD1A. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-477. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-538 and K-547. 5 Publications1
Mutagenesisi538K → R: No change in sumoylation, but reduced ubiquitination. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-532 and K-547. 3 Publications1
Mutagenesisi547K → R: No change in sumoylation, but reduced ubiquitination. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-532 and K-538. 3 Publications1
Mutagenesisi551S → G: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination. 1 Publication1
Mutagenesisi552T → A: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination. 1 Publication1
Mutagenesisi564P → A: Increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation; when associated with A-402. 3 Publications1
Mutagenesisi564P → G: No change in VHL-dependent ubiquitination. Partially reduced VHLE target site ubiquitination. No VHLE target site ubiquitination; when associated with A-402. 3 Publications1
Mutagenesisi576S → A: Induces stabilization of the protein. 1 Publication1
Mutagenesisi657S → A: Induces stabilization of the protein. 1 Publication1
Mutagenesisi709K → R: Abolishes SIRT2-mediated deacetylation, increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation. Increases interaction with EGLN1. 1 Publication1
Mutagenesisi719K → T: Dramatic reduction of accumulation in the nucleus in response to hypoxia. 2 Publications1
Mutagenesisi795L → A: Inhibits interaction with EP300 and transactivation activity. 1 Publication1
Mutagenesisi800C → A: Blocks increase in transcriptional activation caused by nitrosylation. 2 Publications1
Mutagenesisi800C → S: Abolishes hypoxia-inducible transcriptional activation of ctaD. 2 Publications1
Mutagenesisi803N → A: Recruits CREBBP. No enhancement of CREBBP by Clioquinol in the presence of FIH1. No change in nuclear location nor on repression of transcriptional activity in the presence of histone deacetylase inhibitor. 2 Publications1

Organism-specific databases

DisGeNETi3091.
OpenTargetsiENSG00000100644.
PharmGKBiPA29283.

Chemistry databases

ChEMBLiCHEMBL4261.
DrugBankiDB01136. Carvedilol.

Polymorphism and mutation databases

BioMutaiHIF-1A.
DMDMi2498017.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001272201 – 826Hypoxia-inducible factor 1-alphaAdd BLAST826

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei247Phosphoserine; by CK11 Publication1
Cross-linki391Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)2 Publications
Modified residuei4024-hydroxyproline1 Publication1
Cross-linki477Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)2 Publications
Modified residuei532N6-acetyllysine1 Publication1
Cross-linki532Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki538Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Cross-linki547Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei551Phosphoserine; by GSK3-beta1 Publication1
Modified residuei555Phosphothreonine; by GSK3-beta1 Publication1
Modified residuei5644-hydroxyproline4 Publications1
Modified residuei576Phosphoserine; by PLK31 Publication1
Modified residuei589Phosphoserine; by GSK3-beta1 Publication1
Modified residuei657Phosphoserine; by PLK31 Publication1
Modified residuei709N6-acetyllysine1 Publication1
Modified residuei800S-nitrosocysteine1 Publication1
Modified residuei803(3S)-3-hydroxyasparagine1 Publication1

Post-translational modificationi

In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1. EGLN3/PHD3 has also been shown to hydroxylate Pro-564. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization.5 Publications
In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol.1 Publication
S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.2 Publications
Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding. Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome.2 Publications
Sumoylated; with SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia. Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation. Desumoylation by SENP1 increases its stability amd transcriptional activity. There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity.4 Publications
Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation (PubMed:12464182). Deacetylation of Lys-709 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (PubMed:24681946).2 Publications
Polyubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803. Ubiquitinated by a CUL2-based E3 ligase.5 Publications
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.

Keywords - PTMi

Acetylation, Hydroxylation, Isopeptide bond, Phosphoprotein, S-nitrosylation, Ubl conjugation

Proteomic databases

MaxQBiQ16665.
PaxDbiQ16665.
PeptideAtlasiQ16665.
PRIDEiQ16665.

PTM databases

iPTMnetiQ16665.
PhosphoSitePlusiQ16665.

Expressioni

Tissue specificityi

Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors. A higher level expression seen in pituitary tumors as compared to the pituitary gland.1 Publication

Inductioni

Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia. Repressed by HIPK2 and LIMD1.3 Publications

Gene expression databases

BgeeiENSG00000100644.
CleanExiHS_HIF1A.
ExpressionAtlasiQ16665. baseline and differential.
GenevisibleiQ16665. HS.

Organism-specific databases

HPAiCAB017442.
HPA001275.

Interactioni

Subunit structurei

Interacts with the HIF1A beta/ARNT subunit; heterodimerization is required for DNA binding. Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability (By similarity). Interacts with EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domains). Interacts with NCOA1, NCOA2, APEX and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation. During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A. Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription. Interacts (Via the ODD domain) with ARD1A; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF1A sumoylation. Interacts with TSGA10 (By similarity). Interacts with HIF3A (By similarity). Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia-mimicking conditions. Interacts with USP20. Interacts with RACK1; promotes HIF1A ubiquitination and proteasome-mediated degradation. Interacts (via N-terminus) with USP19. Interacts with SIRT2. Interacts (deacetylated form) with EGLN1. Interacts with CBFA2T3.By similarity29 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ARP102752EBI-447269,EBI-608057
ARNTP275409EBI-447269,EBI-80809
ARRB1P494073EBI-447269,EBI-743313
CBX4O0025715EBI-447269,EBI-722425
CREBBPQ927932EBI-447269,EBI-81215
E2f7Q6S7F23EBI-447269,EBI-8030813From a different organism.
e2f7Q5RIX92EBI-447269,EBI-8030618From a different organism.
EAF2Q96CJ13EBI-447269,EBI-1245604
EGLN1Q9GZT94EBI-447269,EBI-1174818
EGLN2Q96KS02EBI-447269,EBI-726614
EGLN3Q9H6Z95EBI-447269,EBI-1175354
EP300Q0947216EBI-447269,EBI-447295
HIF1ANQ9NWT66EBI-447269,EBI-745632
KAT2BQ928312EBI-447269,EBI-477430
MTA1Q133306EBI-447269,EBI-714236
OS9Q134389EBI-447269,EBI-725454
PIAS4Q8N2W93EBI-447269,EBI-473160
PKMP14618-17EBI-447269,EBI-4304679
Rbfox3Q8BIF22EBI-447269,EBI-4567146From a different organism.
RorcP51450-22EBI-447269,EBI-4422078From a different organism.
SEPT9Q9UHD8-14EBI-447269,EBI-851558
SP1P080473EBI-447269,EBI-298336
SUMO1P631654EBI-447269,EBI-80140
UBXN7O948883EBI-447269,EBI-1993627
USP8P408182EBI-447269,EBI-1050865
VHLP4033717EBI-447269,EBI-301246

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • histone acetyltransferase binding Source: UniProtKB
  • Hsp90 protein binding Source: BHF-UCL
  • nuclear hormone receptor binding Source: UniProtKB
  • protein heterodimerization activity Source: UniProtKB
  • protein kinase binding Source: UniProtKB
  • transcription factor binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi109338. 159 interactors.
DIPiDIP-29722N.
IntActiQ16665. 80 interactors.
MINTiMINT-133270.
STRINGi9606.ENSP00000338018.

Chemistry databases

BindingDBiQ16665.

Structurei

Secondary structure

1826
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi241 – 246Combined sources6
Beta strandi251 – 255Combined sources5
Helixi258 – 263Combined sources6
Helixi267 – 270Combined sources4
Helixi275 – 277Combined sources3
Turni281 – 283Combined sources3
Helixi284 – 297Combined sources14
Beta strandi298 – 301Combined sources4
Beta strandi305 – 308Combined sources4
Beta strandi310 – 325Combined sources16
Turni327 – 329Combined sources3
Beta strandi332 – 341Combined sources10
Helixi397 – 400Combined sources4
Beta strandi408 – 410Combined sources3
Helixi559 – 562Combined sources4
Turni779 – 783Combined sources5
Helixi784 – 787Combined sources4
Beta strandi789 – 792Combined sources4
Helixi797 – 803Combined sources7
Beta strandi807 – 809Combined sources3
Helixi815 – 822Combined sources8

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1D7Gmodel-D15-73[»]
1H2KX-ray2.15S786-826[»]
1H2LX-ray2.25S786-826[»]
1H2MX-ray2.50S775-826[»]
1L3ENMR-A786-826[»]
1L8CNMR-B776-826[»]
1LM8X-ray1.85H556-575[»]
1LQBX-ray2.00D549-582[»]
2ILMX-ray2.30S786-826[»]
3HQRX-ray2.00S558-574[»]
3HQUX-ray2.30S558-574[»]
4AJYX-ray1.73H559-577[»]
4H6JX-ray1.52A238-348[»]
5L9BX-ray1.95C/D556-574[»]
5L9VX-ray1.83C/D395-411[»]
5LA9X-ray2.81C/D395-411[»]
5LASX-ray2.10C/D395-411[»]
DisProtiDP00262.
ProteinModelPortaliQ16665.
SMRiQ16665.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ16665.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini17 – 70bHLHPROSITE-ProRule annotationAdd BLAST54
Domaini85 – 158PAS 1PROSITE-ProRule annotationAdd BLAST74
Domaini228 – 298PAS 2PROSITE-ProRule annotationAdd BLAST71
Domaini302 – 345PACAdd BLAST44

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 401Interaction with TSGA10By similarityAdd BLAST401
Regioni380 – 417N-terminal VHL recognition siteAdd BLAST38
Regioni401 – 603ODDAdd BLAST203
Regioni531 – 575NTADAdd BLAST45
Regioni556 – 572C-terminal VHL recognition siteAdd BLAST17
Regioni576 – 785IDAdd BLAST210
Regioni786 – 826CTADAdd BLAST41

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi718 – 721Nuclear localization signalSequence analysis4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi615 – 621Poly-Thr7

Domaini

Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).

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.
InParanoidiQ16665.
KOiK08268.
OMAiYCFDVDS.
OrthoDBiEOG091G0486.
PhylomeDBiQ16665.
TreeFamiTF317772.

Family and domain databases

InterProiIPR011598. bHLH_dom.
IPR001321. HIF-1_alpha.
IPR014887. HIF-1_TAD_C.
IPR021537. HIF_alpha_subunit.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]
PRINTSiPR01080. HYPOXIAIF1A.
SMARTiSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsiTIGR00229. sensory_box. 2 hits.
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: Q16665-1) [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
MEGAGGANDK KKISSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV
60 70 80 90 100
SSHLDKASVM RLTISYLRVR KLLDAGDLDI EDDMKAQMNC FYLKALDGFV
110 120 130 140 150
MVLTDDGDMI YISDNVNKYM GLTQFELTGH SVFDFTHPCD HEEMREMLTH
160 170 180 190 200
RNGLVKKGKE QNTQRSFFLR MKCTLTSRGR TMNIKSATWK VLHCTGHIHV
210 220 230 240 250
YDTNSNQPQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK TFLSRHSLDM
260 270 280 290 300
KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV
310 320 330 340 350
TTGQYRMLAK RGGYVWVETQ ATVIYNTKNS QPQCIVCVNY VVSGIIQHDL
360 370 380 390 400
IFSLQQTECV LKPVESSDMK MTQLFTKVES EDTSSLFDKL KKEPDALTLL
410 420 430 440 450
APAAGDTIIS LDFGSNDTET DDQQLEEVPL YNDVMLPSPN EKLQNINLAM
460 470 480 490 500
SPLPTAETPK PLRSSADPAL NQEVALKLEP NPESLELSFT MPQIQDQTPS
510 520 530 540 550
PSDGSTRQSS PEPNSPSEYC FYVDSDMVNE FKLELVEKLF AEDTEAKNPF
560 570 580 590 600
STQDTDLDLE MLAPYIPMDD DFQLRSFDQL SPLESSSASP ESASPQSTVT
610 620 630 640 650
VFQQTQIQEP TANATTTTAT TDELKTVTKD RMEDIKILIA SPSPTHIHKE
660 670 680 690 700
TTSATSSPYR DTQSRTASPN RAGKGVIEQT EKSHPRSPNV LSVALSQRTT
710 720 730 740 750
VPEEELNPKI LALQNAQRKR KMEHDGSLFQ AVGIGTLLQQ PDDHAATTSL
760 770 780 790 800
SWKRVKGCKS SEQNGMEQKT IILIPSDLAC RLLGQSMDES GLPQLTSYDC
810 820
EVNAPIQGSR NLLQGEELLR ALDQVN
Length:826
Mass (Da):92,670
Last modified:November 1, 1996 - v1
Checksum:iABD4F7DAA135BE2D
GO
Isoform 2 (identifier: Q16665-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     735-735: G → I
     736-826: Missing.

Note: No experimental confirmation available.
Show »
Length:735
Mass (Da):82,746
Checksum:i34DD604FB4E4418E
GO
Isoform 3 (identifier: Q16665-3) [UniParc]FASTAAdd to basket
Also known as: I.3

The sequence of this isoform differs from the canonical sequence as follows:
     1-12: MEGAGGANDKKK → MSSQCRSLENKFVFLKEGLGNSKPEELEEIRIENGR

Note: Up-regulated in peripheral T-lymphocytes after T-cell receptor stimulation. Highest expression in peripheral blood leukocytes and thymus.
Show »
Length:850
Mass (Da):95,634
Checksum:i272C9EFAFD7A1E48
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti572F → L in AAC68568 (PubMed:9782081).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_049541582P → S.Corresponds to variant rs11549465dbSNPEnsembl.1
Natural variantiVAR_049542588A → T.Corresponds to variant rs11549467dbSNPEnsembl.1
Natural variantiVAR_015854796T → A.Corresponds to variant rs1802821dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0449421 – 12MEGAG…NDKKK → MSSQCRSLENKFVFLKEGLG NSKPEELEEIRIENGR in isoform 3. 1 PublicationAdd BLAST12
Alternative sequenceiVSP_047335735G → I in isoform 2. 1 Publication1
Alternative sequenceiVSP_007738736 – 826Missing in isoform 2. 1 PublicationAdd BLAST91

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U22431 mRNA. Translation: AAC50152.1.
U29165 mRNA. Translation: AAC51210.1.
AF050127
, AF050115, AF050116, AF050117, AF050118, AF050119, AF050120, AF050121, AF050122, AF050123, AF050124, AF050125, AF050126 Genomic DNA. Translation: AAC68568.1.
FJ790247 mRNA. Translation: ACN88547.1.
AF207601 mRNA. Translation: AAF20139.1.
AF207602 mRNA. Translation: AAF20140.1.
AF208487 Genomic DNA. Translation: AAF20149.1.
AF304431 mRNA. Translation: AAG43026.1.
AB073325 mRNA. Translation: BAB70608.1.
BT009776 mRNA. Translation: AAP88778.1.
AL137129 Genomic DNA. No translation available.
BC012527 mRNA. Translation: AAH12527.1.
CCDSiCCDS58324.1. [Q16665-3]
CCDS9753.1. [Q16665-1]
CCDS9754.1. [Q16665-2]
PIRiI38972.
RefSeqiNP_001230013.1. NM_001243084.1. [Q16665-3]
NP_001521.1. NM_001530.3. [Q16665-1]
NP_851397.1. NM_181054.2. [Q16665-2]
UniGeneiHs.597216.
Hs.719495.

Genome annotation databases

EnsembliENST00000323441; ENSP00000323326; ENSG00000100644. [Q16665-2]
ENST00000337138; ENSP00000338018; ENSG00000100644. [Q16665-1]
ENST00000539097; ENSP00000437955; ENSG00000100644. [Q16665-3]
GeneIDi3091.
KEGGihsa:3091.
UCSCiuc001xfq.3. human. [Q16665-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

Wikipedia

Hypoxia inducible factor entry

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U22431 mRNA. Translation: AAC50152.1.
U29165 mRNA. Translation: AAC51210.1.
AF050127
, AF050115, AF050116, AF050117, AF050118, AF050119, AF050120, AF050121, AF050122, AF050123, AF050124, AF050125, AF050126 Genomic DNA. Translation: AAC68568.1.
FJ790247 mRNA. Translation: ACN88547.1.
AF207601 mRNA. Translation: AAF20139.1.
AF207602 mRNA. Translation: AAF20140.1.
AF208487 Genomic DNA. Translation: AAF20149.1.
AF304431 mRNA. Translation: AAG43026.1.
AB073325 mRNA. Translation: BAB70608.1.
BT009776 mRNA. Translation: AAP88778.1.
AL137129 Genomic DNA. No translation available.
BC012527 mRNA. Translation: AAH12527.1.
CCDSiCCDS58324.1. [Q16665-3]
CCDS9753.1. [Q16665-1]
CCDS9754.1. [Q16665-2]
PIRiI38972.
RefSeqiNP_001230013.1. NM_001243084.1. [Q16665-3]
NP_001521.1. NM_001530.3. [Q16665-1]
NP_851397.1. NM_181054.2. [Q16665-2]
UniGeneiHs.597216.
Hs.719495.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1D7Gmodel-D15-73[»]
1H2KX-ray2.15S786-826[»]
1H2LX-ray2.25S786-826[»]
1H2MX-ray2.50S775-826[»]
1L3ENMR-A786-826[»]
1L8CNMR-B776-826[»]
1LM8X-ray1.85H556-575[»]
1LQBX-ray2.00D549-582[»]
2ILMX-ray2.30S786-826[»]
3HQRX-ray2.00S558-574[»]
3HQUX-ray2.30S558-574[»]
4AJYX-ray1.73H559-577[»]
4H6JX-ray1.52A238-348[»]
5L9BX-ray1.95C/D556-574[»]
5L9VX-ray1.83C/D395-411[»]
5LA9X-ray2.81C/D395-411[»]
5LASX-ray2.10C/D395-411[»]
DisProtiDP00262.
ProteinModelPortaliQ16665.
SMRiQ16665.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109338. 159 interactors.
DIPiDIP-29722N.
IntActiQ16665. 80 interactors.
MINTiMINT-133270.
STRINGi9606.ENSP00000338018.

Chemistry databases

BindingDBiQ16665.
ChEMBLiCHEMBL4261.
DrugBankiDB01136. Carvedilol.

PTM databases

iPTMnetiQ16665.
PhosphoSitePlusiQ16665.

Polymorphism and mutation databases

BioMutaiHIF-1A.
DMDMi2498017.

Proteomic databases

MaxQBiQ16665.
PaxDbiQ16665.
PeptideAtlasiQ16665.
PRIDEiQ16665.

Protocols and materials databases

DNASUi3091.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000323441; ENSP00000323326; ENSG00000100644. [Q16665-2]
ENST00000337138; ENSP00000338018; ENSG00000100644. [Q16665-1]
ENST00000539097; ENSP00000437955; ENSG00000100644. [Q16665-3]
GeneIDi3091.
KEGGihsa:3091.
UCSCiuc001xfq.3. human. [Q16665-1]

Organism-specific databases

CTDi3091.
DisGeNETi3091.
GeneCardsiHIF1A.
HGNCiHGNC:4910. HIF1A.
HPAiCAB017442.
HPA001275.
MIMi603348. gene.
neXtProtiNX_Q16665.
OpenTargetsiENSG00000100644.
PharmGKBiPA29283.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG3558. Eukaryota.
ENOG410YK57. LUCA.
GeneTreeiENSGT00760000118788.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiQ16665.
KOiK08268.
OMAiYCFDVDS.
OrthoDBiEOG091G0486.
PhylomeDBiQ16665.
TreeFamiTF317772.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000100644-MONOMER.
ReactomeiR-HSA-1234158. Regulation of gene expression by Hypoxia-inducible Factor.
R-HSA-1234162. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
R-HSA-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
R-HSA-1368108. BMAL1:CLOCK,NPAS2 activates circadian gene expression.
R-HSA-2122947. NOTCH1 Intracellular Domain Regulates Transcription.
R-HSA-400253. Circadian Clock.
R-HSA-5689880. Ub-specific processing proteases.
R-HSA-8849473. PTK6 Expression.
R-HSA-8857538. PTK6 promotes HIF1A stabilization.
SignaLinkiQ16665.
SIGNORiQ16665.

Miscellaneous databases

ChiTaRSiHIF1A. human.
EvolutionaryTraceiQ16665.
GeneWikiiHIF1A.
GenomeRNAii3091.
PROiQ16665.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000100644.
CleanExiHS_HIF1A.
ExpressionAtlasiQ16665. baseline and differential.
GenevisibleiQ16665. HS.

Family and domain databases

InterProiIPR011598. bHLH_dom.
IPR001321. HIF-1_alpha.
IPR014887. HIF-1_TAD_C.
IPR021537. HIF_alpha_subunit.
IPR001610. PAC.
IPR000014. PAS.
IPR013767. PAS_fold.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF00989. PAS. 1 hit.
PF08447. PAS_3. 1 hit.
[Graphical view]
PRINTSiPR01080. HYPOXIAIF1A.
SMARTiSM00353. HLH. 1 hit.
SM00086. PAC. 1 hit.
SM00091. PAS. 2 hits.
[Graphical view]
SUPFAMiSSF47459. SSF47459. 1 hit.
SSF55785. SSF55785. 2 hits.
TIGRFAMsiTIGR00229. sensory_box. 2 hits.
PROSITEiPS50888. BHLH. 1 hit.
PS50112. PAS. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHIF1A_HUMAN
AccessioniPrimary (citable) accession number: Q16665
Secondary accession number(s): C0LZJ3
, Q53XP6, Q96PT9, Q9UPB1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: November 30, 2016
This is version 200 of the entry and version 1 of the sequence. [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, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: 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
  6. 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.