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

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dc.citation.articleNumber102349en_US
dc.citation.issueNumber9en_US
dc.citation.journalTitleJournal of Biological Chemistryen_US
dc.citation.volumeNumber298en_US
dc.contributor.authorBaughman, Hannah E.R.en_US
dc.contributor.authorNarang, Dominicen_US
dc.contributor.authorChen, Weien_US
dc.contributor.authorVillagrán Suárez, Amalia C.en_US
dc.contributor.authorLee, Joanen_US
dc.contributor.authorBachochin, Maxwell J.en_US
dc.contributor.authorGunther, Tristan R.en_US
dc.contributor.authorWolynes, Peter G.en_US
dc.contributor.authorKomives, Elizabeth A.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2022-09-08T14:39:54Zen_US
dc.date.available2022-09-08T14:39:54Zen_US
dc.date.issued2022en_US
dc.description.abstractMany transcription factors contain intrinsically disordered transcription activation domains (TADs), which mediate interactions with coactivators to activate transcription. Historically, DNA-binding domains and TADs have been considered as modular units, but recent studies have shown that TADs can influence DNA binding. Whether these results can be generalized to more TADs is not clear. Here, we biophysically characterized the NFκB p50/RelA heterodimer including the RelA TAD and investigated the TAD’s influence on NFκB–DNA interactions. In solution, we show the RelA TAD is disordered but compact, with helical tendency in two regions that interact with coactivators. We determined that the presence of the TAD increased the stoichiometry of NFκB–DNA complexes containing promoter DNA sequences with tandem κB recognition motifs by promoting the binding of NFκB dimers in excess of the number of κB sites. In addition, we measured the binding affinity of p50/RelA for DNA containing tandem κB sites and single κB sites. While the presence of the TAD enhanced the binding affinity of p50/RelA for all κB sequences tested, it also increased the affinity for nonspecific DNA sequences by over 10-fold, leading to an overall decrease in specificity for κB DNA sequences. In contrast, previous studies have generally reported that TADs decrease DNA-binding affinity and increase sequence specificity. Our results reveal a novel function of the RelA TAD in promoting binding to nonconsensus DNA, which sheds light on previous observations of extensive nonconsensus DNA binding by NFκB in vivo in response to strong inflammatory signals.en_US
dc.identifier.citationBaughman, Hannah E.R., Narang, Dominic, Chen, Wei, et al.. "An intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelA." <i>Journal of Biological Chemistry,</i> 298, no. 9 (2022) Elsevier: https://doi.org/10.1016/j.jbc.2022.102349.en_US
dc.identifier.digital1-s2-0-S002192582200792X-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.jbc.2022.102349en_US
dc.identifier.urihttps://hdl.handle.net/1911/113184en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).en_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/).en_US
dc.titleAn intrinsically disordered transcription activation domain increases the DNA binding affinity and reduces the specificity of NFκB p50/RelAen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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