HIF1A_BOVIN
ID HIF1A_BOVIN Reviewed; 823 AA.
AC Q9XTA5;
DT 03-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 168.
DE RecName: Full=Hypoxia-inducible factor 1-alpha;
DE Short=HIF-1-alpha;
DE Short=HIF1-alpha;
GN Name=HIF1A;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Artery;
RX PubMed=10320777; DOI=10.1016/s0167-4781(99)00048-2;
RA Hara S., Kobayashi C., Imura N.;
RT "Molecular cloning of cDNAs encoding hypoxia-inducible factor (HIF)-1alpha
RT and -2alpha of bovine arterial endothelial cells.";
RL Biochim. Biophys. Acta 1445:237-243(1999).
CC -!- FUNCTION: Functions as a master transcriptional regulator of the
CC adaptive response to hypoxia. Under hypoxic conditions, activates the
CC transcription of over 40 genes, including erythropoietin, glucose
CC transporters, glycolytic enzymes, vascular endothelial growth factor,
CC HILPDA, and other genes whose protein products increase oxygen delivery
CC or facilitate metabolic adaptation to hypoxia. Plays an essential role
CC in embryonic vascularization, tumor angiogenesis and pathophysiology of
CC ischemic disease (By similarity). Heterodimerizes with ARNT;
CC heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia
CC response element (HRE) of target gene promoters (By similarity).
CC Activation requires recruitment of transcriptional coactivators such as
CC CREBBP and EP300. Activity is enhanced by interaction with NCOA1 and/or
CC NCOA2. Interaction with redox regulatory protein APEX1 seems to
CC activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved
CC in the axonal distribution and transport of mitochondria in neurons
CC during hypoxia (By similarity). {ECO:0000250|UniProtKB:Q16665,
CC ECO:0000250|UniProtKB:Q61221}.
CC -!- ACTIVITY REGULATION: Induced by reactive oxygen species (ROS).
CC {ECO:0000250|UniProtKB:Q16665}.
CC -!- SUBUNIT: Interacts with the ARNT; forms a heterodimer that binds core
CC DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of
CC target gene promoters (By similarity). Interacts with COPS5; the
CC interaction increases the transcriptional activity of HIF1A through
CC increased stability (By similarity). Interacts with EP300 (via TAZ-type
CC 1 domains); the interaction is stimulated in response to hypoxia and
CC inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domains).
CC Interacts with NCOA1, NCOA2, APEX1 and HSP90. Interacts (hydroxylated
CC within the ODD domain) with VHLL (via beta domain); the interaction,
CC leads to polyubiquitination and subsequent HIF1A proteasomal
CC degradation. During hypoxia, sumoylated HIF1A also binds VHL; the
CC interaction promotes the ubiquitination of HIF1A (By similarity).
CC Interacts with SENP1; the interaction desumoylates HIF1A resulting in
CC stabilization and activation of transcription (By similarity).
CC Interacts (via the ODD domain) with NAA10; the interaction appears not
CC to acetylate HIF1A nor have any affect on protein stability, during
CC hypoxia. Interacts with RWDD3; the interaction enhances HIF1A
CC sumoylation (By similarity). Interacts with TSGA10. Interacts with
CC HIF3A (By similarity). Interacts with RORA (via the DNA binding
CC domain); the interaction enhances HIF1A transcription under hypoxia
CC through increasing protein stability. Interaction with PSMA7 inhibits
CC the transactivation activity of HIF1A under both normoxic and hypoxia-
CC mimicking conditions. Interacts with USP20. Interacts with RACK1;
CC promotes HIF1A ubiquitination and proteasome-mediated degradation.
CC Interacts (via N-terminus) with USP19. Interacts with SIRT2. Interacts
CC (deacetylated form) with EGLN1. Interacts with CBFA2T3. Interacts with
CC HSP90AA1 and HSP90AB1. Interacts with DCUN1D1; this interaction
CC increases the interaction between VHL and DCUN1D1. Interacts with
CC HIF1AN (By similarity). {ECO:0000250|UniProtKB:Q16665,
CC ECO:0000250|UniProtKB:Q61221}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q16665}. Nucleus
CC {ECO:0000250|UniProtKB:Q61221}. Note=Colocalizes with HIF3A in the
CC nucleus and speckles (By similarity). Cytoplasmic in normoxia, nuclear
CC translocation in response to hypoxia (By similarity).
CC {ECO:0000250|UniProtKB:Q16665, ECO:0000250|UniProtKB:Q61221}.
CC -!- DOMAIN: Contains two independent C-terminal transactivation domains,
CC NTAD and CTAD, which function synergistically. Their transcriptional
CC activity is repressed by an intervening inhibitory domain (ID) (By
CC similarity). {ECO:0000250|UniProtKB:Q16665}.
CC -!- PTM: S-nitrosylation of Cys-797 may be responsible for increased
CC recruitment of p300 coactivator necessary for transcriptional activity
CC of HIF-1 complex. {ECO:0000250|UniProtKB:Q16665}.
CC -!- PTM: Acetylation of Lys-532 by ARD1 increases interaction with VHL and
CC stimulates subsequent proteasomal degradation. Deacetylation of Lys-706
CC by SIRT2 increases its interaction with and hydroxylation by EGLN1
CC thereby inactivating HIF1A activity by inducing its proteasomal
CC degradation (By similarity). {ECO:0000250|UniProtKB:Q16665}.
CC -!- PTM: Requires phosphorylation for DNA-binding. Phosphorylation at Ser-
CC 247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding.
CC Phosphorylation by GSK3-beta and PLK3 promote degradation by the
CC proteasome (By similarity). {ECO:0000250|UniProtKB:Q16665,
CC ECO:0000250|UniProtKB:Q61221}.
CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of
CC asparagine is (S) stereospecific within HIF CTAD domains.
CC {ECO:0000250|UniProtKB:Q16665}.
CC -!- PTM: Sumoylated; with SUMO1 under hypoxia. Sumoylation is enhanced
CC through interaction with RWDD3. Both sumoylation and desumoylation seem
CC to be involved in the regulation of its stability during hypoxia.
CC Sumoylation can promote either its stabilization or its VHL-dependent
CC degradation by promoting hydroxyproline-independent HIF1A-VHL complex
CC binding, thus leading to HIF1A ubiquitination and proteasomal
CC degradation. Desumoylation by SENP1 increases its stability amd
CC transcriptional activity. There is a disaccord between various
CC publications on the effect of sumoylation and desumoylation on its
CC stability and transcriptional activity (By similarity).
CC {ECO:0000250|UniProtKB:Q16665, ECO:0000250|UniProtKB:Q61221}.
CC -!- PTM: In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-
CC dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1.
CC EGLN3/PHD3 has also been shown to hydroxylate Pro-564. The hydroxylated
CC prolines promote interaction with VHL, initiating rapid ubiquitination
CC and subsequent proteasomal degradation. Deubiquitinated by USP20. Under
CC hypoxia, proline hydroxylation is impaired and ubiquitination is
CC attenuated, resulting in stabilization (By similarity). In normoxia, is
CC hydroxylated on Asn-800 by HIF1AN, thus abrogating interaction with
CC CREBBP and EP300 and preventing transcriptional activation. Repressed
CC by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated
CC hydroxylation and subsequent proteasomal degradation.
CC {ECO:0000250|UniProtKB:Q16665}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB018398; BAA78675.1; -; mRNA.
DR AlphaFoldDB; Q9XTA5; -.
DR SMR; Q9XTA5; -.
DR STRING; 9913.ENSBTAP00000027885; -.
DR PaxDb; Q9XTA5; -.
DR PRIDE; Q9XTA5; -.
DR eggNOG; KOG3558; Eukaryota.
DR InParanoid; Q9XTA5; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0001223; F:transcription coactivator binding; ISS:UniProtKB.
DR GO; GO:0019896; P:axonal transport of mitochondrion; ISS:UniProtKB.
DR GO; GO:0001678; P:cellular glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0071456; P:cellular response to hypoxia; ISS:UniProtKB.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0061419; P:positive regulation of transcription from RNA polymerase II promoter in response to hypoxia; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0006110; P:regulation of glycolytic process; ISS:UniProtKB.
DR GO; GO:2000434; P:regulation of protein neddylation; ISS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; ISS:UniProtKB.
DR GO; GO:0000302; P:response to reactive oxygen species; ISS:UniProtKB.
DR CDD; cd00130; PAS; 2.
DR Gene3D; 4.10.280.10; -; 1.
DR InterPro; IPR011598; bHLH_dom.
DR InterPro; IPR001321; HIF-1_alpha.
DR InterPro; IPR014887; HIF-1_TAD_C.
DR InterPro; IPR021537; HIF_alpha_subunit.
DR InterPro; IPR036638; HLH_DNA-bd_sf.
DR InterPro; IPR001610; PAC.
DR InterPro; IPR000014; PAS.
DR InterPro; IPR035965; PAS-like_dom_sf.
DR InterPro; IPR013767; PAS_fold.
DR InterPro; IPR013655; PAS_fold_3.
DR Pfam; PF11413; HIF-1; 1.
DR Pfam; PF08778; HIF-1a_CTAD; 1.
DR Pfam; PF00989; PAS; 1.
DR Pfam; PF08447; PAS_3; 1.
DR PRINTS; PR01080; HYPOXIAIF1A.
DR SMART; SM00353; HLH; 1.
DR SMART; SM00086; PAC; 1.
DR SMART; SM00091; PAS; 2.
DR SUPFAM; SSF47459; SSF47459; 1.
DR SUPFAM; SSF55785; SSF55785; 2.
DR TIGRFAMs; TIGR00229; sensory_box; 2.
DR PROSITE; PS50888; BHLH; 1.
DR PROSITE; PS50112; PAS; 2.
PE 2: Evidence at transcript level;
KW Acetylation; Activator; Cytoplasm; DNA-binding; Hydroxylation;
KW Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; Repeat;
KW S-nitrosylation; Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..823
FT /note="Hypoxia-inducible factor 1-alpha"
FT /id="PRO_0000127219"
FT DOMAIN 17..70
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 85..158
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 228..298
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 302..345
FT /note="PAC"
FT REGION 1..401
FT /note="Interaction with TSGA10"
FT /evidence="ECO:0000250|UniProtKB:Q61221"
FT REGION 1..30
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 21..30
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q61221"
FT REGION 170..191
FT /note="Required for heterodimer formation with ARNT"
FT /evidence="ECO:0000250|UniProtKB:Q61221"
FT REGION 401..600
FT /note="ODD"
FT REGION 494..521
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 531..575
FT /note="NTAD"
FT REGION 576..782
FT /note="ID"
FT REGION 581..602
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 639..685
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 783..823
FT /note="CTAD"
FT MOTIF 715..721
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 494..516
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 652..666
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 247
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 402
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 532
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 551
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 555
FT /note="Phosphothreonine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 564
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 576
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 589
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 654
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 706
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 797
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 800
FT /note="(3S)-3-hydroxyasparagine"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT CROSSLNK 532
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT CROSSLNK 538
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT CROSSLNK 547
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
SQ SEQUENCE 823 AA; 92128 MW; 12674E467A61B1A1 CRC64;
MEGAGGANDK KKISSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV SSHLDKASVM
RLTISYLRVR KLLDAGDLDI EDEMKAQMNC FYLKALDGFV MVLTDDGDMI YISDNVNKYM
GLTQFELTGH SVFDFTHPCD HEEMREMLTH RNGLVKKGKE QNTQRSFFLR MKCTLTSRGR
TMNIKSATWK VLHCTGHIHV YDTNSNQSQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK
TFLSRHSLDM KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV
TTGQYRMLAK RGGYVWIETQ ATVIYNTKNS QPQCIVCVNY VVSGIIQHDL IFSLQQTECV
LKPVESSDMK MTQLFTKVES EDTSSLFDKL KKEPDALTLL APAAGDTIIS LDFGSNDTET
DDQQLEEVPL YNDVMLPSSN EKLQNINLAM SPLPASETPK PLRSSADPAL NQEVALKLEP
NPESLELSFT MPQIQDQPAS PSDGSTRQSS PEPNSPSEYC FDVDSDMVNE FKLELVEKLF
AEDTEAKNPF STQDTDLDLE MLAPYIPMDD DFQLRSFDQL SPLENSSTSP QSASTNTVFQ
PTQMQKPPIA TVTTTATSDE LKTVTKDGME DIKILIAFPS PPHVPKEPPC ATTSPYSDTG
SRTASPNRAG KGVIEQTEKS HPRSPNVLSV ALSQRTTAPE EELNPKILAL QNAQRKRKIE
HDGSLFQAVG IGTLLQQPDD RATTTSLSWK RVKGCKSSEQ NGMEQKTIIL IPSDLACRLL
GQSMDESGLP QLTSYDCEVN APIQGSRNLL QGEELLRALD QVN
