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Protein

Hypoxia-inducible factor 1-alpha

Gene

Hif1a

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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. 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 CREBPB 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

GO - Biological processi

  • acute-phase response Source: RGD
  • axon transport of mitochondrion Source: UniProtKB
  • cellular response to carbon monoxide Source: RGD
  • cellular response to cobalt ion Source: RGD
  • cellular response to cyanide Source: RGD
  • cellular response to drug Source: RGD
  • cellular response to electrical stimulus Source: RGD
  • cellular response to glucose stimulus Source: RGD
  • cellular response to hydrogen peroxide Source: RGD
  • cellular response to hypoxia Source: UniProtKB
  • cellular response to insulin stimulus Source: RGD
  • cellular response to interleukin-1 Source: RGD
  • cellular response to light stimulus Source: RGD
  • cellular response to lipid Source: RGD
  • cellular response to lipopolysaccharide Source: RGD
  • cellular response to mechanical stimulus Source: RGD
  • cellular response to nitrite Source: RGD
  • cellular response to organic cyclic compound Source: RGD
  • cellular response to toxic substance Source: RGD
  • maternal process involved in female pregnancy Source: RGD
  • negative regulation of apoptotic process Source: RGD
  • negative regulation of transcription from RNA polymerase II promoter Source: RGD
  • negative regulation of vasoconstriction Source: RGD
  • positive regulation of apoptotic process Source: RGD
  • positive regulation of cell proliferation Source: RGD
  • positive regulation of cell size Source: RGD
  • positive regulation of gene expression Source: RGD
  • positive regulation of gluconeogenesis Source: RGD
  • positive regulation of smooth muscle cell proliferation Source: RGD
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: RGD
  • 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
  • regulation of cellular response to hypoxia Source: RGD
  • regulation of transcription, DNA-templated Source: RGD
  • regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: RGD
  • response to activity Source: RGD
  • response to alkaloid Source: RGD
  • response to anesthetic Source: RGD
  • response to auditory stimulus Source: RGD
  • response to cobalt ion Source: RGD
  • response to drug Source: RGD
  • response to estradiol Source: RGD
  • response to estrogen Source: RGD
  • response to fungicide Source: RGD
  • response to glucocorticoid Source: RGD
  • response to glucose Source: RGD
  • response to hypoxia Source: UniProtKB
  • response to mechanical stimulus Source: RGD
  • response to purine-containing compound Source: RGD
  • response to salt stress Source: RGD
  • response to X-ray Source: RGD
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Activator

Keywords - Biological processi

Transcription, Transcription regulation

Keywords - Ligandi

DNA-binding

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi61928. Hif1a.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus
  • Nucleus speckle By similarity

  • Note: Colocalizes with HIF3A in the nucleus and speckles (By similarity). Cytoplasmic in normoxia, nuclear translocation in response to hypoxia (By similarity).By similarity

GO - Cellular componenti

  • axon cytoplasm Source: GOC
  • cytoplasm Source: RGD
  • cytosol Source: UniProtKB
  • nuclear speck Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 825825Hypoxia-inducible factor 1-alphaPRO_0000127222Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei247 – 2471Phosphoserine; by CK1By similarity
Modified residuei402 – 40214-hydroxyprolineBy similarity
Modified residuei531 – 5311N6-acetyllysineBy similarity
Modified residuei550 – 5501Phosphoserine; by GSK3-betaBy similarity
Modified residuei554 – 5541Phosphothreonine; by GSK3-betaBy similarity
Modified residuei563 – 56314-hydroxyprolineBy similarity
Modified residuei575 – 5751Phosphoserine; by PLK3By similarity
Modified residuei588 – 5881Phosphoserine; by GSK3-betaBy similarity
Modified residuei657 – 6571Phosphoserine; by PLK3By similarity
Modified residuei802 – 8021(3S)-3-hydroxyasparagineBy similarity

Post-translational modificationi

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).By similarity
In normoxia, is hydroxylated on Asn-802 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.By similarity
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

Keywords - PTMi

Acetylation, Hydroxylation, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiO35800.
PRIDEiO35800.

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. Efficient DNA binding requires heterodimerization of an alpha and a beta/ARNT subunit. 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.By similarity

GO - Molecular functioni

  • histone acetyltransferase binding Source: UniProtKB
  • protein complex binding Source: RGD
  • protein heterodimerization activity Source: UniProtKB
  • ubiquitin protein ligase binding Source: RGD

Protein-protein interaction databases

BioGridi248194. 6 interactions.
IntActiO35800. 1 interaction.
MINTiMINT-235713.
STRINGi10116.ENSRNOP00000042230.

Structurei

3D structure databases

ProteinModelPortaliO35800.
SMRiO35800. Positions 237-345, 775-825.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini17 – 7054bHLHPROSITE-ProRule annotationAdd
BLAST
Domaini85 – 15874PAS 1PROSITE-ProRule annotationAdd
BLAST
Domaini228 – 29871PAS 2PROSITE-ProRule annotationAdd
BLAST
Domaini302 – 34544PACAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni1 – 401401Interaction with TSGA10By similarityAdd
BLAST
Regioni401 – 602202ODDAdd
BLAST
Regioni530 – 57445NTADAdd
BLAST
Regioni575 – 784210IDAdd
BLAST
Regioni785 – 82541CTADAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi717 – 7215Nuclear localization signalSequence analysis

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

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.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiO35800.
KOiK08268.

Family and domain databases

InterProiIPR011598. bHLH_dom.
IPR001321. HIF-1_alpha.
IPR014887. HIF-1_TAD_C.
IPR021537. HIF_alpha_subunit.
IPR001610. PAC.
IPR000014. PAS.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF08447. PAS_3. 1 hit.
PF13426. PAS_9. 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]

Sequencei

Sequence statusi: Complete.

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

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti12 – 121K → NR in AAD24413 (PubMed:11526200).Curated
Sequence conflicti74 – 741D → G in AAD24413 (PubMed:11526200).Curated
Sequence conflicti96 – 961P → L in AAD24413 (PubMed:11526200).Curated
Sequence conflicti329 – 3291D → N in AAD24413 (PubMed:11526200).Curated
Sequence conflicti613 – 6197ATATTAT → TATA in AAD24413 (PubMed:11526200).Curated
Sequence conflicti708 – 7081R → K in AAD24413 (PubMed:11526200).Curated

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.

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. Positions 237-345, 775-825.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi248194. 6 interactions.
IntActiO35800. 1 interaction.
MINTiMINT-235713.
STRINGi10116.ENSRNOP00000042230.

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

PROiO35800.

Family and domain databases

InterProiIPR011598. bHLH_dom.
IPR001321. HIF-1_alpha.
IPR014887. HIF-1_TAD_C.
IPR021537. HIF_alpha_subunit.
IPR001610. PAC.
IPR000014. PAS.
IPR013655. PAS_fold_3.
[Graphical view]
PfamiPF11413. HIF-1. 1 hit.
PF08778. HIF-1a_CTAD. 1 hit.
PF08447. PAS_3. 1 hit.
PF13426. PAS_9. 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...

Publicationsi

  1. "Perivenous expression of the mRNA of the three hypoxia-inducible factor a-subunits HIF-1a, HIF2a and HIF3a in rat liver."
    Kietzmann T., Cornesse Y., Brechtel K., Modaressi S., Jungermann K.
    Biochem. J. 354:531-537(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Wistar.
    Tissue: Hepatocyte.
  2. "Oxygen-dependent expression of hypoxia-inducible factor-1alpha in renal medullary cells of rats."
    Zou A.-P., Yang Z.-Z., Li P.-L., Cowley A.W. Jr.
    Physiol. Genomics 6:159-168(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Sprague-Dawley.
    Tissue: Kidney.

Entry informationi

Entry nameiHIF1A_RAT
AccessioniPrimary (citable) accession number: O35800
Secondary accession number(s): Q9WTU9
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 3, 2003
Last sequence update: January 1, 1998
Last modified: July 6, 2016
This is version 151 of the entry and version 1 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. 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.