An intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelA

• DOI: 10.1016/j.jbc.2022.102349
• Publication Date: 2022-08-05T02:34:05Z
• Authors: Hannah E.R. Baughman; Dominic Narang; Wei Chen; Amalia C. Villagr...; Joan Lee; Maxwell J. Bachochin; Tristan R. Gunther; Peter G. Wolynes; Elizabeth A. Komives
• Keywords: Transcription; HMG-box; DNA binding site

Many transcription factors contain intrinsically disordered activation domains (TADs), which mediate interactions with coactivators to activate transcription. Historically, DNA-binding and TADs have been considered as modular units, but recent studies shown that can influence DNA binding. Whether these results be generalized more is not clear. Here, we biophysically characterized the NFκB p50/RelA heterodimer including RelA TAD investigated TAD's on NFκB-DNA interactions. In solution, show compact, helical tendency in two regions interact coactivators. We determined presence of increased stoichiometry complexes containing promoter sequences tandem κB recognition motifs by promoting binding dimers excess number sites. addition, measured affinity for sites single While enhanced all tested, it also nonspecific over 10-fold, leading an overall decrease specificity sequences. contrast, previous generally reported increase sequence specificity. Our reveal a novel function nonconsensus DNA, sheds light observations extensive vivo response strong inflammatory signals.