HIF1A_EOSFB
ID HIF1A_EOSFB Reviewed; 819 AA.
AC Q309Z6;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 06-DEC-2005, sequence version 1.
DT 25-MAY-2022, entry version 100.
DE RecName: Full=Hypoxia-inducible factor 1-alpha;
DE Short=HIF-1-alpha;
DE Short=HIF1-alpha;
GN Name=HIF1A;
OS Eospalax fontanierii baileyi (Plateau zokor) (Eospalax baileyi).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Spalacidae; Myospalacinae; Eospalax.
OX NCBI_TaxID=146132;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Chen X.-Q., Xie Z.-Y., Du J.-Z.;
RT "Cloning of hypoxia-inducible factor 1 alpha from plateau zokor (Myospalax
RT baileyi).";
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
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}. Nucleus
CC {ECO:0000250|UniProtKB:Q61221, ECO:0000255|PROSITE-ProRule:PRU00981}.
CC Nucleus speckle {ECO:0000250|UniProtKB:Q61221}. Note=Colocalizes with
CC HIF3A in the nucleus and speckles. Cytoplasmic in normoxia, nuclear
CC translocation in response to hypoxia. {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-793 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-533 by ARD1 increases interaction with VHL and
CC stimulates subsequent proteasomal degradation. Deacetylation of Lys-702
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 248 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-403 and Pro-565 in the oxygen-
CC dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1.
CC EGLN3/PHD3 has also been shown to hydroxylate Pro-565. 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-796 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}.
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DR EMBL; DQ229099; ABB17537.1; -; mRNA.
DR AlphaFoldDB; Q309Z6; -.
DR SMR; Q309Z6; -.
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; ISS: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: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; Repeat; S-nitrosylation;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..819
FT /note="Hypoxia-inducible factor 1-alpha"
FT /id="PRO_0000254948"
FT DOMAIN 18..71
FT /note="bHLH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981"
FT DOMAIN 86..159
FT /note="PAS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 229..299
FT /note="PAS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 303..346
FT /note="PAC"
FT REGION 1..402
FT /note="Interaction with TSGA10"
FT /evidence="ECO:0000250|UniProtKB:Q61221"
FT REGION 1..31
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 22..31
FT /note="DNA-binding"
FT /evidence="ECO:0000250|UniProtKB:Q61221"
FT REGION 171..192
FT /note="Required for heterodimer formation with ARNT"
FT /evidence="ECO:0000250|UniProtKB:Q61221"
FT REGION 402..599
FT /note="ODD"
FT REGION 495..521
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 532..576
FT /note="NTAD"
FT REGION 577..778
FT /note="ID"
FT REGION 581..685
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 779..819
FT /note="CTAD"
FT MOTIF 711..717
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 495..517
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 581..617
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 625..685
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 248
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 403
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 533
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 552
FT /note="Phosphoserine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 556
FT /note="Phosphothreonine; by GSK3-beta"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 565
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 577
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 650
FT /note="Phosphoserine; by PLK3"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 702
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 793
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT MOD_RES 796
FT /note="(3S)-3-hydroxyasparagine"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT CROSSLNK 533
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT CROSSLNK 539
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
FT CROSSLNK 548
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q16665"
SQ SEQUENCE 819 AA; 91660 MW; 5BC90BD0FD279FE8 CRC64;
MEGAAGGEEK KNRMSSERRK EKSRDAARSR RSKESEVFYE LAHQLPLPHN VSSHLDKASV
MRLTISYLRV RKLLDAGDLD IEDDMKAQMN CFYLKALDGF VMVLTDDGDM IYISDNVNKY
MGLTQFELTG HSVFDFTHPC DHEEMREMLT HRNGPIKKGK EQNTQRSFFL RMKCTLTSRG
RTMNIKSATW KVLHCTGHIH VYDTNSNQPQ CGYKKPPMTC LVLICEPIPH PSNIEIPLDS
KTFLSRHSLD MKFSYCDERI TELMGYEPEE LLGRSIYEYY HALDSDHLTK THHDMFTKGQ
VTTGQYRMLA KRGGYVWVET QATVIYNTKN SQPQCIVCVN YVVSGIIQHD LIFSLQQTEC
VLKPVESSDM KMTQLFTKVE SEDTSCLFDK LKKEPDALTL LAPAAGDTII SLDFGSDDTE
TEDQQLEDVP LYNDVMFPSS DDKLTSINLA MSPLPASETP KPLRSNADPA LNQEVALKLE
PNAESLELSF TMPQIQDQPA SPSDGSTRQS SPEPNSPSEY CFDVDSDMVN VFKLELVEKL
FAEDTEAKNP FSTQDTDLDL EMLAPYIPMD DDFQLRSFDQ LSPLESSSPN PPSVSTAFQQ
TQLQEPTITT TTTEELKTVT KDSTEDIKIL ITSPSSTHTP KETTTATTSS PYSGTQSRTA
SPNRAGQGVI EQTEKSHPRS PNVLSVTLSQ RNTVPEEELN PKIIALQNAQ RKRKMEHDGS
LFQAAGIGTL LQQPDDRAPA TSLSWKRVKG CKSSGQNGME QKTIILIPSD LACRLLGQSM
DGSGLPQLTS YDCEVNAPIQ GSRNLLQGEE LLRALDQVN
