Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Hypoxia-inducible factor 1-alpha

Gene

HIF1A

Organism
Bos taurus (Bovine)
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

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
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Unplaced

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus 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
  • 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 – 823823Hypoxia-inducible factor 1-alphaPRO_0000127219Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei247 – 2471Phosphoserine; by CK1By similarity
Modified residuei402 – 40214-hydroxyprolineBy similarity
Modified residuei532 – 5321N6-acetyllysineBy similarity
Modified residuei551 – 5511Phosphoserine; by GSK3-betaBy similarity
Modified residuei555 – 5551Phosphothreonine; by GSK3-betaBy similarity
Modified residuei564 – 56414-hydroxyprolineBy similarity
Modified residuei576 – 5761Phosphoserine; by PLK3By similarity
Modified residuei589 – 5891Phosphoserine; by GSK3-betaBy similarity
Modified residuei654 – 6541Phosphoserine; by PLK3By similarity
Modified residuei706 – 7061N6-acetyllysineBy similarity
Modified residuei800 – 8001(3S)-3-hydroxyasparagineBy similarity

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 (By similarity).By similarity
In normoxia, is hydroxylated on Asn-800 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.By similarity
S-nitrosylation of Cys-797 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.By similarity
Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation. Deacetylation of Lys-706 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

PaxDbiQ9XTA5.
PRIDEiQ9XTA5.

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 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 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

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000027885.

Structurei

3D structure databases

ProteinModelPortaliQ9XTA5.
SMRiQ9XTA5. Positions 237-345, 773-823.
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 – 600200ODDAdd
BLAST
Regioni531 – 57545NTADAdd
BLAST
Regioni576 – 782207IDAdd
BLAST
Regioni783 – 82341CTADAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi715 – 7217Nuclear 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.
InParanoidiQ9XTA5.

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]

Sequencei

Sequence statusi: Complete.

Q9XTA5-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MEGAGGANDK KKISSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV
60 70 80 90 100
SSHLDKASVM RLTISYLRVR KLLDAGDLDI EDEMKAQMNC 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
YDTNSNQSQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK TFLSRHSLDM
260 270 280 290 300
KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV
310 320 330 340 350
TTGQYRMLAK RGGYVWIETQ ATVIYNTKNS QPQCIVCVNY VVSGIIQHDL
360 370 380 390 400
IFSLQQTECV LKPVESSDMK MTQLFTKVES EDTSSLFDKL KKEPDALTLL
410 420 430 440 450
APAAGDTIIS LDFGSNDTET DDQQLEEVPL YNDVMLPSSN EKLQNINLAM
460 470 480 490 500
SPLPASETPK PLRSSADPAL NQEVALKLEP NPESLELSFT MPQIQDQPAS
510 520 530 540 550
PSDGSTRQSS PEPNSPSEYC FDVDSDMVNE FKLELVEKLF AEDTEAKNPF
560 570 580 590 600
STQDTDLDLE MLAPYIPMDD DFQLRSFDQL SPLENSSTSP QSASTNTVFQ
610 620 630 640 650
PTQMQKPPIA TVTTTATSDE LKTVTKDGME DIKILIAFPS PPHVPKEPPC
660 670 680 690 700
ATTSPYSDTG SRTASPNRAG KGVIEQTEKS HPRSPNVLSV ALSQRTTAPE
710 720 730 740 750
EELNPKILAL QNAQRKRKIE HDGSLFQAVG IGTLLQQPDD RATTTSLSWK
760 770 780 790 800
RVKGCKSSEQ NGMEQKTIIL IPSDLACRLL GQSMDESGLP QLTSYDCEVN
810 820
APIQGSRNLL QGEELLRALD QVN
Length:823
Mass (Da):92,128
Last modified:November 1, 1999 - v1
Checksum:i12674E467A61B1A1
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB018398 mRNA. Translation: BAA78675.1.
UniGeneiBt.4184.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB018398 mRNA. Translation: BAA78675.1.
UniGeneiBt.4184.

3D structure databases

ProteinModelPortaliQ9XTA5.
SMRiQ9XTA5. Positions 237-345, 773-823.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000027885.

Proteomic databases

PaxDbiQ9XTA5.
PRIDEiQ9XTA5.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Phylogenomic databases

eggNOGiKOG3558. Eukaryota.
ENOG410YK57. LUCA.
HOGENOMiHOG000234306.
HOVERGENiHBG060456.
InParanoidiQ9XTA5.

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...

Publicationsi

  1. "Molecular cloning of cDNAs encoding hypoxia-inducible factor (HIF)-1alpha and -2alpha of bovine arterial endothelial cells."
    Hara S., Kobayashi C., Imura N.
    Biochim. Biophys. Acta 1445:237-243(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Artery.

Entry informationi

Entry nameiHIF1A_BOVIN
AccessioniPrimary (citable) accession number: Q9XTA5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 3, 2003
Last sequence update: November 1, 1999
Last modified: July 6, 2016
This is version 135 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.