| Structural highlights
Function
[CBP_MOUSE] Acetylates histones, giving a specific tag for transcriptional activation. Also acetylates non-histone proteins, like NCOA3 and FOXO1. Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1 in the presence of EP300 (By similarity).[1] [2] [3] [4] [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.[5] [6] [7] [8] [9] [10] [11] [12] [13]
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
The cellular response to low tissue oxygen concentrations is mediated by the hypoxia-inducible transcription factor HIF-1. Under hypoxic conditions, HIF-1 activates transcription of critical adaptive genes by recruitment of the general coactivators CBP/p300 through interactions with its alpha-subunit (Hif-1 alpha). Disruption of the Hif-1 alpha/p300 interaction has been linked to attenuation of tumor growth. To delineate the structural basis for this interaction, we have determined the solution structure of the complex between the carboxy-terminal activation domain (CAD) of Hif-1 alpha and the zinc-binding TAZ1 (CH1) motif of cyclic-AMP response element binding protein (CREB) binding protein (CBP). Despite the overall similarity of the TAZ1 structure to that of the TAZ2 (part of the CH3) domain of CBP, differences occur in the packing of helices that can account for differences in specificity. The unbound CAD is intrinsically disordered and remains relatively extended upon binding, wrapping almost entirely around the TAZ1 domain in a groove through much of its surface. Three short helices are formed upon binding, stabilized by intermolecular interactions. The Asn-803 side chain, which functions as a hypoxic switch, is located on the second of these helices and is buried in the molecular interface. The third helix of the Hif-1 alpha CAD docks in a deep hydrophobic groove in TAZ1, providing extensive intermolecular hydrophobic interactions that contribute to the stability of the complex. The structure of this complex provides new insights into the mechanism through which Hif-1 alpha recruits CBP/p300 in response to hypoxia.
Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response.,Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, Wright PE Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5271-6. PMID:11959977[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hung HL, Lau J, Kim AY, Weiss MJ, Blobel GA. CREB-Binding protein acetylates hematopoietic transcription factor GATA-1 at functionally important sites. Mol Cell Biol. 1999 May;19(5):3496-505. PMID:10207073
- ↑ Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, Montminy M, Evans RM. A transcriptional switch mediated by cofactor methylation. Science. 2001 Dec 21;294(5551):2507-11. Epub 2001 Nov 8. PMID:11701890 doi:10.1126/science.1065961
- ↑ Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. Epub 2004 Jun 25. PMID:15220471 doi:10.1073/pnas.0400593101
- ↑ Kuo HY, Chang CC, Jeng JC, Hu HM, Lin DY, Maul GG, Kwok RP, Shih HM. SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):16973-8. Epub 2005 Nov 15. PMID:16287980 doi:10.1073/pnas.0504460102
- ↑ 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
- ↑ Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, Wright PE. Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5271-6. PMID:11959977 doi:http://dx.doi.org/10.1073/pnas.082121399
|
