UniProt Accession

 HIF1A_HUMAN; Q16665; C0LZJ3; Q53XP6; Q96PT9; Q9UPB1 

Genbank Protein ID

 U22431; U29165; AF050127; AF050115; AF050116; AF050117; AF050118; AF050119; AF050120; AF050121; AF050122; AF050123; AF050124; AF050125; AF050126; FJ790247; AF207601; AF207602; AF208487; AF304431; AB073325; BT009776; AL137129; BC012527 

Genbank Nucleotide ID

 AAC50152.1; AAC51210.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; AAC68568.1; ACN88547.1; AAF20139.1; AAF20140.1; AAF20149.1; AAG43026.1; BAB70608.1; AAP88778.1; AAH12527.1 

Protein Name

 Hypoxia-inducible factor 1-alpha 

Protein Synonyms/Alias

 HIF-1-alpha; HIF1-alpha; ARNT-interacting protein; Basic-helix-loop-helix-PAS protein MOP1; Class E basic helix-loop-helix protein 78; bHLHe78; Member of PAS protein 1; PAS domain-containing protein 8 

Gene Name

 HIF1A 

Gene Synonyms/Alias

 BHLHE78; MOP1; PASD8 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
10	GAGGANDKKKISSER	acetylation	[1]
10	GAGGANDKKKISSER	ubiquitination	[2]
11	AGGANDKKKISSERR	acetylation	[1]
11	AGGANDKKKISSERR	ubiquitination	[2]
12	GGANDKKKISSERRK	acetylation	[1]
12	GGANDKKKISSERRK	ubiquitination	[2]
19	KISSERRKEKSRDAA	acetylation	[1]
21	SSERRKEKSRDAARS	acetylation	[1]
32	AARSRRSKESEVFYE	ubiquitination	[2, 3]
71	ISYLRVRKLLDAGDL	ubiquitination	[2, 3]
172	RSFFLRMKCTLTSRG	ubiquitination	[2]
185	RGRTMNIKSATWKVL	ubiquitination	[2, 3, 4]
251	SRHSLDMKFSYCDER	ubiquitination	[2, 4]
289	LDSDHLTKTHHDMFT	ubiquitination	[2, 3]
297	THHDMFTKGQVTTGQ	ubiquitination	[2, 3, 4]
377	KMTQLFTKVESEDTS	ubiquitination	[2, 3, 4]
389	DTSSLFDKLKKEPDA	ubiquitination	[2, 3]
391	SSLFDKLKKEPDALT	sumoylation	[5, 6, 7]
391	SSLFDKLKKEPDALT	ubiquitination	[3]
392	SLFDKLKKEPDALTL	ubiquitination	[2]
477	LNQEVALKLEPNPES	sumoylation	[5, 6, 7]
477	LNQEVALKLEPNPES	ubiquitination	[3]
532	SDMVNEFKLELVEKL	acetylation	[8]
538	FKLELVEKLFAEDTE	ubiquitination	[3, 4, 9, 10]
674	ASPNRAGKGVIEQTE	acetylation	[11]
674	ASPNRAGKGVIEQTE	ubiquitination	[3]
709	PEEELNPKILALQNA	acetylation	[12]
709	PEEELNPKILALQNA	ubiquitination	[2, 3, 4]
769	EQNGMEQKTIILIPS	ubiquitination	[2]

Reference

 [1] HDAC4 protein regulates HIF1α protein lysine acetylation and cancer cell response to hypoxia.
 Geng H, Harvey CT, Pittsenbarger J, Liu Q, Beer TM, Xue C, Qian DZ.
 J Biol Chem. 2011 Nov 4;286(44):38095-102. [PMID: 21917920]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [4] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
 Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
 J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]
 [5] Sumoylation increases HIF-1alpha stability and its transcriptional activity.
 Bae SH, Jeong JW, Park JA, Kim SH, Bae MK, Choi SJ, Kim KW.
 Biochem Biophys Res Commun. 2004 Nov 5;324(1):394-400. [PMID: 15465032]
 [6] SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity.
 Berta MA, Mazure N, Hattab M, Pouysségur J, Brahimi-Horn MC.
 Biochem Biophys Res Commun. 2007 Aug 31;360(3):646-52. [PMID: 17610843]
 [7] In vivo identification of human small ubiquitin-like modifier polymerization sites by high accuracy mass spectrometry and an in vitro to in vivo strategy.
 Matic I, van Hagen M, Schimmel J, Macek B, Ogg SC, Tatham MH, Hay RT, Lamond AI, Mann M, Vertegaal AC.
 Mol Cell Proteomics. 2008 Jan;7(1):132-44. [PMID: 17938407]
 [8] Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation.
 Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, Kim KW.
 Cell. 2002 Nov 27;111(5):709-20. [PMID: 12464182]
 [9] Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry.
 Meierhofer D, Wang X, Huang L, Kaiser P.
 J Proteome Res. 2008 Oct;7(10):4566-76. [PMID: 18781797]
 [10] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [11] Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha.
 Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW.
 Mol Cell. 2010 Jun 25;38(6):864-78. [PMID: 20620956]
 [12] HIF1α protein stability is increased by acetylation at lysine 709.
 Geng H, Liu Q, Xue C, David LL, Beer TM, Thomas GV, Dai MS, Qian DZ.
 J Biol Chem. 2012 Oct 12;287(42):35496-505. [PMID: 22908229] 

Functional Description

 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. 

Sequence Annotation

 DOMAIN 17 70 bHLH.
 DOMAIN 85 158 PAS 1.
 DOMAIN 228 298 PAS 2.
 DOMAIN 302 345 PAC.
 REGION 1 401 Interaction with TSGA10 (By similarity).
 REGION 380 417 N-terminal VHL recognition site.
 REGION 401 603 ODD.
 REGION 531 575 NTAD.
 REGION 556 572 C-terminal VHL recognition site.
 REGION 576 785 ID.
 REGION 786 826 CTAD.
 MOTIF 718 721 Nuclear localization signal (Potential).
 MOD_RES 247 247 Phosphoserine; by CK1.
 MOD_RES 402 402 4-hydroxyproline.
 MOD_RES 551 551 Phosphoserine; by GSK3-beta.
 MOD_RES 555 555 Phosphothreonine; by GSK3-beta.
 MOD_RES 564 564 4-hydroxyproline.
 MOD_RES 576 576 Phosphoserine; by PLK3.
 MOD_RES 589 589 Phosphoserine; by GSK3-beta.
 MOD_RES 657 657 Phosphoserine; by PLK3.
 MOD_RES 800 800 S-nitrosocysteine (Probable).
 MOD_RES 803 803 (3S)-3-hydroxyasparagine.
 CROSSLNK 391 391 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 477 477 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 532 532 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 538 538 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 547 547 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Activator; Alternative splicing; Complete proteome; Cytoplasm; Direct protein sequencing; DNA-binding; Hydroxylation; Isopeptide bond; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Repeat; S-nitrosylation; Transcription; Transcription regulation; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 826 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005730; C:nucleolus; IDA:HPA.
 GO:0005667; C:transcription factor complex; IPI:MGI.
 GO:0051879; F:Hsp90 protein binding; IDA:BHF-UCL.
 GO:0000988; F:protein binding transcription factor activity; IDA:BHF-UCL.
 GO:0046982; F:protein heterodimerization activity; TAS:UniProtKB.
 GO:0001077; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; IEA:Compara.
 GO:0003705; F:RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity; IDA:BHF-UCL.
 GO:0043565; F:sequence-specific DNA binding; IEA:Compara.
 GO:0004871; F:signal transducer activity; IEA:InterPro.
 GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB.
 GO:0001525; P:angiogenesis; IEA:Compara.
 GO:0019896; P:axon transport of mitochondrion; IMP:UniProtKB.
 GO:0001922; P:B-1 B cell homeostasis; IEA:Compara.
 GO:0003208; P:cardiac ventricle morphogenesis; IEA:Compara.
 GO:0051216; P:cartilage development; IEA:Compara.
 GO:0006879; P:cellular iron ion homeostasis; IEA:Compara.
 GO:0071347; P:cellular response to interleukin-1; IEP:BHF-UCL.
 GO:0021987; P:cerebral cortex development; IEA:Compara.
 GO:0032963; P:collagen metabolic process; ISS:BHF-UCL.
 GO:0002248; P:connective tissue replacement involved in inflammatory response wound healing; ISS:BHF-UCL.
 GO:0048546; P:digestive tract morphogenesis; IEA:Compara.
 GO:0071542; P:dopaminergic neuron differentiation; IEA:Compara.
 GO:0051541; P:elastin metabolic process; ISS:BHF-UCL.
 GO:0035162; P:embryonic hemopoiesis; IEA:Compara.
 GO:0001892; P:embryonic placenta development; IEA:Compara.
 GO:0061030; P:epithelial cell differentiation involved in mammary gland alveolus development; IEA:Compara.
 GO:0001837; P:epithelial to mesenchymal transition; ISS:BHF-UCL.
 GO:0042593; P:glucose homeostasis; IEA:Compara.
 GO:0001947; P:heart looping; IEA:Compara.
 GO:0042541; P:hemoglobin biosynthetic process; IEA:Compara.
 GO:0060574; P:intestinal epithelial cell maturation; IEA:Compara.
 GO:0006089; P:lactate metabolic process; IEA:Compara.
 GO:0007595; P:lactation; IEA:Compara.
 GO:0042789; P:mRNA transcription from RNA polymerase II promoter; IC:BHF-UCL.
 GO:0046716; P:muscle cell homeostasis; IEA:Compara.
 GO:0030502; P:negative regulation of bone mineralization; IEA:Compara.
 GO:0045926; P:negative regulation of growth; IEA:Compara.
 GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; IEA:Compara.
 GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Compara.
 GO:0032007; P:negative regulation of TOR signaling cascade; IEA:Compara.
 GO:0001755; P:neural crest cell migration; IEA:Compara.
 GO:0021502; P:neural fold elevation formation; IEA:Compara.
 GO:0007219; P:Notch signaling pathway; TAS:Reactome.
 GO:0003151; P:outflow tract morphogenesis; IEA:Compara.
 GO:0032364; P:oxygen homeostasis; IDA:HGNC.
 GO:0045766; P:positive regulation of angiogenesis; IC:BHF-UCL.
 GO:0032722; P:positive regulation of chemokine production; TAS:BHF-UCL.
 GO:0070101; P:positive regulation of chemokine-mediated signaling pathway; IC:BHF-UCL.
 GO:0001938; P:positive regulation of endothelial cell proliferation; IC:BHF-UCL.
 GO:0010634; P:positive regulation of epithelial cell migration; ISS:BHF-UCL.
 GO:0045648; P:positive regulation of erythrocyte differentiation; IC:BHF-UCL.
 GO:0045821; P:positive regulation of glycolysis; IC:BHF-UCL.
 GO:0046886; P:positive regulation of hormone biosynthetic process; IDA:BHF-UCL.
 GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Compara.
 GO:0002052; P:positive regulation of neuroblast proliferation; IEA:Compara.
 GO:0051000; P:positive regulation of nitric-oxide synthase activity; TAS:BHF-UCL.
 GO:0010870; P:positive regulation of receptor biosynthetic process; IMP:BHF-UCL.
 GO:0061419; P:positive regulation of transcription from RNA polymerase II promoter in response to hypoxia; IDA:BHF-UCL.
 GO:0030949; P:positive regulation of vascular endothelial growth factor receptor signaling pathway; IC:BHF-UCL.
 GO:0010575; P:positive regulation vascular endothelial growth factor production; IDA:BHF-UCL.
 GO:0043619; P:regulation of transcription from RNA polymerase II promoter in response to oxidative stress; IDA:BHF-UCL.
 GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL.
 GO:0014850; P:response to muscle activity; IEA:Compara.
 GO:0061298; P:retina vasculature development in camera-type eye; IEA:Compara.
 GO:0010573; P:vascular endothelial growth factor production; IDA:BHF-UCL.
 GO:0008542; P:visual learning; IEA:Compara. 

Interpro

 IPR011598; 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. 

Pfam

 PF11413; HIF-1
 PF08778; HIF-1a_CTAD
 PF00989; PAS
 PF08447; PAS_3 

SMART

 SM00353; HLH
 SM00086; PAC
 SM00091; PAS 

PROSITE

 PS50888; BHLH
 PS50113; PAC
 PS50112; PAS 

PRINTS

 PR01080; HYPOXIAIF1A.