2LWW

NMR structure of RelA-TAD/CBP-TAZ1 complex

Summary for 2LWW

• Entry DOI: 10.2210/pdb2lww/pdb
• NMR Information: BMRB: 18650
• Descriptor: CREB-binding protein, Nuclear transcription factor RelA, ZINC ION (3 entities in total)
• Functional Keywords: nf-kappab, p65, transcription
• Biological source: Mus musculus (mouse); More
• Cellular location: Cytoplasm (By similarity): P45481
• Total number of polymer chains: 2
• Total formula weight: 18800.25

Authors

Mukherjee, S.P.,Ghosh, G.,Wright, P.E. (deposition date: 2012-08-07, release date: 2013-09-11, Last modification date: 2024-05-01)

Primary citation

Mukherjee, S.P.,Behar, M.,Birnbaum, H.A.,Hoffmann, A.,Wright, P.E.,Ghosh, G.
Analysis of the RelA:CBP/p300 Interaction Reveals Its Involvement in NF-kappa B-Driven Transcription.
Plos Biol., 11:e1001647-e1001647, 2013

PubMed Abstract: NF-κB 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-κB family member) interacts with transcriptional co-activators like CREB-binding protein (CBP) and its paralog p300 in addition to its cognate κB 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-κB through the negative feedback loop of NF-κB 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.

PubMed: 24019758
DOI: 10.1371/journal.pbio.1001647

Experimental method

SOLUTION NMR