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Protein

Hypoxia-inducible factor 1-alpha

Gene

Hif1a

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at transcript 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. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). 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 (By similarity).By similarity

GO - Molecular functioni

  • DNA-binding transcription factor activity Source: UniProtKB
  • DNA-binding transcription factor activity, RNA polymerase II-specific Source: GO_Central
  • histone acetyltransferase binding Source: UniProtKB
  • protein-containing complex binding Source: RGD
  • protein heterodimerization activity Source: RGD
  • sequence-specific DNA binding Source: RGD
  • ubiquitin protein ligase binding Source: RGD

GO - Biological processi

Keywordsi

Molecular functionActivator, DNA-binding
Biological processTranscription, Transcription regulation

Names & Taxonomyi

Protein namesi
Recommended name:
Hypoxia-inducible factor 1-alpha
Short name:
HIF-1-alpha
Short name:
HIF1-alpha
Gene namesi
Name:Hif1a
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi61928 Hif1a

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, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001272221 – 825Hypoxia-inducible factor 1-alphaAdd BLAST825

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei247Phosphoserine; by CK1By similarity1
Modified residuei4024-hydroxyprolineBy similarity1
Modified residuei531N6-acetyllysine; alternateBy similarity1
Cross-linki531Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternateBy similarity
Cross-linki537Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki546Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei550Phosphoserine; by GSK3-betaBy similarity1
Modified residuei554Phosphothreonine; by GSK3-betaBy similarity1
Modified residuei5634-hydroxyprolineBy similarity1
Modified residuei575Phosphoserine; by PLK3By similarity1
Modified residuei588Phosphoserine; by GSK3-betaBy similarity1
Modified residuei657Phosphoserine; by PLK3By similarity1
Modified residuei799S-nitrosocysteineBy similarity1
Modified residuei802(3S)-3-hydroxyasparagineBy similarity1

Post-translational modificationi

S-nitrosylation of Cys-799 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.By similarity
Acetylation of Lys-531 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation. Deacetylated by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (By similarity).By similarity
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 (By similarity).By similarity
The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.By similarity
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 (By similarity).By similarity
In normoxia, is hydroxylated on Pro-402 and Pro-563 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1. EGLN3/PHD3 has also been shown to hydroxylate Pro-563. 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 (By similarity). In normoxia, is hydroxylated on Asn-802 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. Repressed by iron ion, via Fe2+ prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation.By similarity

Keywords - PTMi

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

Proteomic databases

PaxDbiO35800
PRIDEiO35800

PTM databases

PhosphoSitePlusiO35800

Expressioni

Tissue specificityi

Expressed in the kidney, higher expression is seen in the renal medulla than in the cortex. Expressed also in the perivenous zone of the liver.

Interactioni

Subunit structurei

Interacts with COPS5 subunit of COP9 signalosome complex, leading to the regulation of its stability. Interacts with the ARNT; forms a heterodimer that binds core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Interacts with NCOA1, NCOA2, APEX, HSP90 and TSGA10. Interacts with VHL which docks HFA1 to the E3 ubiquitin ligase complex for subsequent destruction. Interaction, via the ODD domain, with the beta domain of VHLL, protects HIF1A from destruction by competing against the destructive targeting initiated by VHL. Interacts with RORA (via the DNA bi nding 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 with EP300 (via TAZ-type 1 domain); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domain). Interacts (via N-terminus) with USP19. Interacts with SIRT2. Interacts (deacetylated form) with EGLN1. Interacts with RWDD3; the interaction enhances HIF1A sumoylation. Interacts with HIF3A. Interacts with CBFA2T3. Interacts with HSP90AA1 and HSP90AB1.By similarity

GO - Molecular functioni

Protein-protein interaction databases

BioGridi248194, 7 interactors
IntActiO35800, 1 interactor
MINTiO35800
STRINGi10116.ENSRNOP00000042230

Structurei

3D structure databases

ProteinModelPortaliO35800
SMRiO35800
ModBaseiSearch...
MobiDBiSearch...

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
Regioni21 – 30DNA-bindingBy similarity10
Regioni170 – 191Required for heterodimer formation with ARNTBy similarityAdd BLAST22
Regioni401 – 602ODDAdd BLAST202
Regioni530 – 574NTADAdd BLAST45
Regioni575 – 784IDAdd BLAST210
Regioni785 – 825CTADAdd BLAST41

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi717 – 721Nuclear localization signalSequence analysis5

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) (By similarity).By similarity

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG3558 Eukaryota
ENOG410YK57 LUCA
HOGENOMiHOG000234306
HOVERGENiHBG060456
InParanoidiO35800
KOiK08268

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
IPR001321 HIF-1_alpha
IPR014887 HIF-1_TAD_C
IPR021537 HIF_alpha_subunit
IPR036638 HLH_DNA-bd_sf
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013655 PAS_fold_3
PfamiView protein in Pfam
PF11413 HIF-1, 1 hit
PF08778 HIF-1a_CTAD, 1 hit
PF08447 PAS_3, 1 hit
PF13426 PAS_9, 1 hit
PRINTSiPR01080 HYPOXIAIF1A
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, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits

Sequence (1+)i

Sequence statusi: Complete.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

O35800-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MEGAGGENEK KKMSSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV
60 70 80 90 100
SSHLDKASVM RLTISYLRVR KLLDAGDLDI EDEMKAQMNC FYLKAPDGFV
110 120 130 140 150
MVLTDDGDMI YISDNVNKYM GLTQFELTGH SVFDFTHPCD HEEMREMLTH
160 170 180 190 200
RNGPVRKGKE QNTQRSFFLR MKCTLTSRGR TMNIKSATWK VLHCTGHIHV
210 220 230 240 250
YDTSSNQPQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK TFLSRHSLDM
260 270 280 290 300
KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV
310 320 330 340 350
TTGQYRMLAK RGGYVWVETQ ATVIYNTKDS QPQCIVCVNY VVSGIIQHDL
360 370 380 390 400
IFSLQQTESV LKPVESSDMK MTQLFTKVES EDTSCLFDKL KKEPDALTLL
410 420 430 440 450
APAAGDTIIS LDFGSDDTET EDQQLEDVPL YNDVMFPSSN EKLNINLAMS
460 470 480 490 500
PLPASETPKP LRSSADPALN QEVALKLESS PESLGLSFTM PQIQDQPASP
510 520 530 540 550
SDGSTRQSSP EPNSPSEYCF DVDSDMVNVF KLELVEKLFA EDTEAKNPFS
560 570 580 590 600
AQDTDLDLEM LAPYIPMDDD FQLRSFDQLS PLESNSPSPP SVSTVTGFQQ
610 620 630 640 650
TQLQKPTITV TAATATTATT TDESKAVTKD NIEDIKILIA SPPSTQVPQE
660 670 680 690 700
MTTAKASAYS GTHSRTASPD RAGKRVIEKT DKAHPRSLNL SVTLNQRNTV
710 720 730 740 750
PEEELNPRTI ALQNAQRKRK MEHDGSLFQA AGIGTLLQQP GDRAPTMSLS
760 770 780 790 800
WKRVKGYISS EQDGMEQKTI FLIPSDLACR LLGQSMDESG LPQLTSYDCE
810 820
VNAPIQGSRN LLQGEELLRA LDQVN
Length:825
Mass (Da):92,319
Last modified:January 1, 1998 - v1
Checksum:iC4109A57F38667E9
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
D4A8P8D4A8P8_RAT
Hypoxia-inducible factor 1-alpha
Hif1a
825Annotation score:
A0A0G2JX87A0A0G2JX87_RAT
Hypoxia-inducible factor 1-alpha
Hif1a
816Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti12K → NR in AAD24413 (PubMed:11526200).Curated1
Sequence conflicti74D → G in AAD24413 (PubMed:11526200).Curated1
Sequence conflicti96P → L in AAD24413 (PubMed:11526200).Curated1
Sequence conflicti329D → N in AAD24413 (PubMed:11526200).Curated1
Sequence conflicti613 – 619ATATTAT → TATA in AAD24413 (PubMed:11526200).Curated7
Sequence conflicti708R → K in AAD24413 (PubMed:11526200).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y09507 mRNA Translation: CAA70701.1
AF057308 mRNA Translation: AAD24413.1
PIRiJC5809
RefSeqiNP_077335.1, NM_024359.1
UniGeneiRn.10852

Genome annotation databases

GeneIDi29560
KEGGirno:29560
UCSCiRGD:61928 rat

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
Y09507 mRNA Translation: CAA70701.1
AF057308 mRNA Translation: AAD24413.1
PIRiJC5809
RefSeqiNP_077335.1, NM_024359.1
UniGeneiRn.10852

3D structure databases

ProteinModelPortaliO35800
SMRiO35800
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi248194, 7 interactors
IntActiO35800, 1 interactor
MINTiO35800
STRINGi10116.ENSRNOP00000042230

PTM databases

PhosphoSitePlusiO35800

Proteomic databases

PaxDbiO35800
PRIDEiO35800

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi29560
KEGGirno:29560
UCSCiRGD:61928 rat

Organism-specific databases

CTDi3091
RGDi61928 Hif1a

Phylogenomic databases

eggNOGiKOG3558 Eukaryota
ENOG410YK57 LUCA
HOGENOMiHOG000234306
HOVERGENiHBG060456
InParanoidiO35800
KOiK08268

Miscellaneous databases

PROiPR:O35800

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
IPR001321 HIF-1_alpha
IPR014887 HIF-1_TAD_C
IPR021537 HIF_alpha_subunit
IPR036638 HLH_DNA-bd_sf
IPR001610 PAC
IPR000014 PAS
IPR035965 PAS-like_dom_sf
IPR013655 PAS_fold_3
PfamiView protein in Pfam
PF11413 HIF-1, 1 hit
PF08778 HIF-1a_CTAD, 1 hit
PF08447 PAS_3, 1 hit
PF13426 PAS_9, 1 hit
PRINTSiPR01080 HYPOXIAIF1A
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, 2 hits
PROSITEiView protein in PROSITE
PS50888 BHLH, 1 hit
PS50112 PAS, 2 hits
ProtoNetiSearch...

Entry informationi

Entry nameiHIF1A_RAT
AccessioniPrimary (citable) accession number: O35800
Secondary accession number(s): Q9WTU9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 3, 2003
Last sequence update: January 1, 1998
Last modified: November 7, 2018
This is version 172 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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