| Structural highlights
2ilm is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| Related: | 1h2k, 1h2l, 1h2n, 1h2m, 1yci |
| Gene: | HIF1AN (HUMAN) |
| Activity: | Peptide-aspartate beta-dioxygenase, with EC number 1.14.11.16 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum |
Function
[HIF1N_HUMAN] Hydroxylates HIF-1 alpha at 'Asp-803' in the C-terminal transactivation domain (CAD). Functions as an oxygen sensor and, under normoxic conditions, the hydroxylation prevents interaction of HIF-1 with transcriptional coactivators including Cbp/p300-interacting transactivator. Involved in transcriptional repression through interaction with HIF1A, VHL and histone deacetylases. Hydroxylates specific Asn residues within ankyrin repeat domains (ARD) of NFKB1, NFKBIA, NOTCH1, ASB4, PPP1R12A and several other ARD-containing proteins. Also hydroxylates Asp and His residues within ARDs of ANK1 and TNKS2, respectively. Negatively regulates NOTCH1 activity, accelerating myogenic differentiation. Positively regulates ASB4 activity, promoting vascular differentiation.[1] [2] [3] [4] [5] [6] [7] [8] [HIF1A_HUMAN] 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.[9] [10] [11] [12] [13] [14] [15] [16] [17]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
A 2-His-1-carboxylate triad of iron binding residues is present in many non-heme iron oxygenases including the Fe(II) and 2-oxoglutarate (2OG)-dependent dioxygenases. Three variants (D201A, D201E, and D201G) of the iron binding Asp-201 residue of an asparaginyl hydroxylase, factor inhibiting HIF (FIH), were made and analyzed. FIH-D201A and FIH-D201E did not catalyze asparaginyl hydroxylation, but in the presence of a reducing agent, they displayed enhanced 2OG turnover when compared with wild-type FIH. Turnover of 2OG by FIH-D201A was significantly stimulated by the addition of HIF-1alpha(786-826) peptide. Like FIH-D201A and D201E, the D201G variant enhanced 2OG turnover but rather unexpectedly catalyzed asparaginyl hydroxylation. Crystal structures of the FIH-D201A and D201G variants in complex with Fe(II)/Zn(II), 2OG, and HIF-1alpha(786-826/788-806) implied that only two FIH-based residues (His-199 and His-279) are required for metal binding. The results indicate that variation of 2OG-dependent dioxygenase iron-ligating residues as a means of functional assignment should be treated with caution. The results are of mechanistic interest in the light of recent biochemical and structural analyses of non-heme iron and 2OG-dependent halogenases that are similar to the FIH-D201A/G variants in that they use only two His-residues to ligate iron.
Evidence that two enzyme-derived histidine ligands are sufficient for iron binding and catalysis by factor inhibiting HIF (FIH).,Hewitson KS, Holmes SL, Ehrismann D, Hardy AP, Chowdhury R, Schofield CJ, McDonough MA J Biol Chem. 2008 Sep 19;283(38):25971-8. Epub 2008 Jul 8. PMID:18611856[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002 Jun 15;16(12):1466-71. PMID:12080085 doi:10.1101/gad.991402
- ↑ Hewitson KS, McNeill LA, Riordan MV, Tian YM, Bullock AN, Welford RW, Elkins JM, Oldham NJ, Bhattacharya S, Gleadle JM, Ratcliffe PJ, Pugh CW, Schofield CJ. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem. 2002 Jul 19;277(29):26351-5. Epub 2002 May 31. PMID:12042299 doi:10.1074/jbc.C200273200
- ↑ Cockman ME, Lancaster DE, Stolze IP, Hewitson KS, McDonough MA, Coleman ML, Coles CH, Yu X, Hay RT, Ley SC, Pugh CW, Oldham NJ, Masson N, Schofield CJ, Ratcliffe PJ. Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14767-72. Epub 2006 Sep 26. PMID:17003112
- ↑ Zheng X, Linke S, Dias JM, Zheng X, Gradin K, Wallis TP, Hamilton BR, Gustafsson M, Ruas JL, Wilkins S, Bilton RL, Brismar K, Whitelaw ML, Pereira T, Gorman JJ, Ericson J, Peet DJ, Lendahl U, Poellinger L. Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3368-73. doi:, 10.1073/pnas.0711591105. Epub 2008 Feb 25. PMID:18299578 doi:10.1073/pnas.0711591105
- ↑ Webb JD, Muranyi A, Pugh CW, Ratcliffe PJ, Coleman ML. MYPT1, the targeting subunit of smooth-muscle myosin phosphatase, is a substrate for the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH). Biochem J. 2009 May 13;420(2):327-33. doi: 10.1042/BJ20081905. PMID:19245366 doi:10.1042/BJ20081905
- ↑ Coleman ML, McDonough MA, Hewitson KS, Coles C, Mecinovic J, Edelmann M, Cook KM, Cockman ME, Lancaster DE, Kessler BM, Oldham NJ, Ratcliffe PJ, Schofield CJ. Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J Biol Chem. 2007 Aug 17;282(33):24027-38. Epub 2007 Jun 15. PMID:17573339 doi:http://dx.doi.org/10.1074/jbc.M704102200
- ↑ Yang M, Chowdhury R, Ge W, Hamed RB, McDonough MA, Claridge TD, Kessler BM, Cockman ME, Ratcliffe PJ, Schofield CJ. Factor-Inhibiting Hypoxia-Inducible Factor (FIH) Catalyses the Posttranslational Hydroxylation of Histidinyl Residues within Ankyrin Repeat Domains. FEBS J. 2011 Jan 20. doi: 10.1111/j.1742-4658.2011.08022.x. PMID:21251231 doi:10.1111/j.1742-4658.2011.08022.x
- ↑ Yang M, Ge W, Chowdhury R, Claridge TD, Kramer HB, Schmierer B, McDonough MA, Gong L, Kessler BM, Ratcliffe PJ, Coleman ML, Schofield CJ. Asparagine and aspartate hydroxylation of the cytoskeletal ankyrin family is catalyzed by factor-inhibiting hypoxia-inducible factor. J Biol Chem. 2011 Mar 4;286(9):7648-60. Epub 2010 Dec 22. PMID:21177872 doi:10.1074/jbc.M110.193540
- ↑ Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev. 1999 Jan 1;13(1):64-75. PMID:9887100
- ↑ Masson N, Willam C, Maxwell PH, Pugh CW, Ratcliffe PJ. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J. 2001 Sep 17;20(18):5197-206. PMID:11566883 doi:10.1093/emboj/20.18.5197
- ↑ Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001 Apr 20;292(5516):468-72. Epub 2001 Apr 5. PMID:11292861 doi:10.1126/science.1059796
- ↑ Bae SH, Jeong JW, Park JA, Kim SH, Bae MK, Choi SJ, Kim KW. Sumoylation increases HIF-1alpha stability and its transcriptional activity. Biochem Biophys Res Commun. 2004 Nov 5;324(1):394-400. PMID:15465032 doi:10.1016/j.bbrc.2004.09.068
- ↑ Fath DM, Kong X, Liang D, Lin Z, Chou A, Jiang Y, Fang J, Caro J, Sang N. Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha. J Biol Chem. 2006 May 12;281(19):13612-9. Epub 2006 Mar 15. PMID:16543236 doi:M600456200
- ↑ Choi SM, Choi KO, Park YK, Cho H, Yang EG, Park H. Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells. J Biol Chem. 2006 Nov 10;281(45):34056-63. Epub 2006 Sep 13. PMID:16973622 doi:M603913200
- ↑ Berta MA, Mazure N, Hattab M, Pouyssegur J, Brahimi-Horn MC. SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity. Biochem Biophys Res Commun. 2007 Aug 31;360(3):646-52. Epub 2007 Jun 27. PMID:17610843 doi:10.1016/j.bbrc.2007.06.103
- ↑ Li Y, Lim S, Hoffman D, Aspenstrom P, Federoff HJ, Rempe DA. HUMMR, a hypoxia- and HIF-1alpha-inducible protein, alters mitochondrial distribution and transport. J Cell Biol. 2009 Jun 15;185(6):1065-81. doi: 10.1083/jcb.200811033. PMID:19528298 doi:10.1083/jcb.200811033
- ↑ Gimm T, Wiese M, Teschemacher B, Deggerich A, Schodel J, Knaup KX, Hackenbeck T, Hellerbrand C, Amann K, Wiesener MS, Honing S, Eckardt KU, Warnecke C. Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1. FASEB J. 2010 Nov;24(11):4443-58. doi: 10.1096/fj.10-159806. Epub 2010 Jul 12. PMID:20624928 doi:10.1096/fj.10-159806
- ↑ Hewitson KS, Holmes SL, Ehrismann D, Hardy AP, Chowdhury R, Schofield CJ, McDonough MA. Evidence that two enzyme-derived histidine ligands are sufficient for iron binding and catalysis by factor inhibiting HIF (FIH). J Biol Chem. 2008 Sep 19;283(38):25971-8. Epub 2008 Jul 8. PMID:18611856 doi:10.1074/jbc.M804999200
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