| 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]
Publication Abstract from PubMed
NF-kappaB plays a vital role in cellular immune and inflammatory response, survival, and proliferation by regulating the transcription of various genes involved in these processes. To activate transcription, RelA (a prominent NF-kappaB family member) interacts with transcriptional co-activators like CREB-binding protein (CBP) and its paralog p300 in addition to its cognate kappaB sites on the promoter/enhancer regions of DNA. The RelA:CBP/p300 complex is comprised of two components-first, DNA binding domain of RelA interacts with the KIX domain of CBP/p300, and second, the transcriptional activation domain (TAD) of RelA binds to the TAZ1 domain of CBP/p300. A phosphorylation event of a well-conserved RelA(Ser276) is prerequisite for the former interaction to occur and is considered a decisive factor for the overall RelA:CBP/p300 interaction. The role of the latter interaction in the transcription of RelA-activated genes remains unclear. Here we provide the solution structure of the latter component of the RelA:CBP complex by NMR spectroscopy. The structure reveals the folding of RelA-TA2 (a section of TAD) upon binding to TAZ1 through its well-conserved hydrophobic sites in a series of grooves on the TAZ1 surface. The structural analysis coupled with the mechanistic studies by mutational and isothermal calorimetric analyses allowed the design of RelA-mutants that selectively abrogated the two distinct components of the RelA:CBP/p300 interaction. Detailed studies of these RelA mutants using cell-based techniques, mathematical modeling, and genome-wide gene expression analysis showed that a major set of the RelA-activated genes, larger than previously believed, is affected by this interaction. We further show how the RelA:CBP/p300 interaction controls the nuclear response of NF-kappaB through the negative feedback loop of NF-kappaB pathway. Additionally, chromatin analyses of RelA target gene promoters showed constitutive recruitment of CBP/p300, thus indicating a possible role of CBP/p300 in recruitment of RelA to its target promoter sites.
Analysis of the RelA:CBP/p300 Interaction Reveals Its Involvement in NF-kappaB-Driven Transcription.,Mukherjee SP, Behar M, Birnbaum HA, Hoffmann A, Wright PE, Ghosh G PLoS Biol. 2013 Sep;11(9):e1001647. doi: 10.1371/journal.pbio.1001647. Epub 2013 , Sep 3. PMID:24019758[5]
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
- ↑ Mukherjee SP, Behar M, Birnbaum HA, Hoffmann A, Wright PE, Ghosh G. Analysis of the RelA:CBP/p300 Interaction Reveals Its Involvement in NF-kappaB-Driven Transcription. PLoS Biol. 2013 Sep;11(9):e1001647. doi: 10.1371/journal.pbio.1001647. Epub 2013 , Sep 3. PMID:24019758 doi:10.1371/journal.pbio.1001647
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