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PreprintCited by 27NF-κB Signaling PathwaysProtein Structure and DynamicsGenomics and Chromatin Dynamics

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

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Baughman, Hannah E.R., Narang, Dominic, Chen, Wei, Villagrán Suárez, Amalia C., Lee, Joan, Bachochin, Maxwell, Gunther, Tristan R., Wolynes, Peter G., Komives, Elizabeth A.·2022·Journal of Biological Chemistry
DOI 10.1101/2022.04.11.487922PMC PMC9440430

Preprint — published as 10.1016/j.jbc.2022.102349 · Paper page

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Abstract

Many transcription factors contain intrinsically disordered transcription activation domains (TADs), which mediate interactions with co-activators 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. We biophysically characterized the NFκB p50/RelA heterodimer including the RelA TAD and investigated the TAD’s influence on NFκB-DNA interactions. In solution the RelA TAD is disordered but compact, with helical tendency in two regions that interact with co-activators. 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. 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 increased the affinity for non-specific DNA sequences by over 10-fold, leading to an overall decrease in specificity for κB DNA sequences. Our results reveal a novel function of the RelA TAD in promoting binding to non-consensus DNA previously observed by in vivo studies of NFκB-DNA binding in response to strong inflammatory signals.

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Metadata

Authors
Baughman, H. E. R., Narang, D., Chen, W., Villagrán Suárez, A. C., Lee, J., Bachochin, M., Gunther, T. R., Wolynes, P. G., & Komives, E. A.
Affiliations
  • University of California San Diego (US)
  • Center for Theoretical Biological Physics (US)
Corresponding author
Komives, Elizabeth A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
openRxiv
Published
2022-04-11
Volume
298
Issue
9
Pages
102349-102349
ISSN
0021-9258 (ISSN-L)
DOI
10.1101/2022.04.11.487922
PMC
PMC9440430
OpenAlex
W4289994798
Cited by
27
References
1
Citations by year
2026: 3 · 2025: 6 · 2024: 9 · 2023: 8 · 2022: 1
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Rice Research Repository (Rice University) (submittedVersion, cc-by)
Funders
  • U.S. Department of Energy (P30 GM124169, GM124169)
  • American Cancer Society (PF-22-073-01-DMC)
  • G. Harold and Leila Y. Mathers Charitable Foundation (K12 GM068524)
  • Scleroderma Foundation-Tri-State
  • Rice University (C-0016)
  • G. Harold and Leila Y. Mathers Foundation (MF-2012-01149)
  • National Institutes of Health (GM071862, GM124169, PO1 GM071862)
  • National Institute of General Medical Sciences (GM-068524, GM 071862, P01GM071862, GM124169, P30GM124169, K12GM068524, R01GM141182, T32GM139795)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
intrinsically disordered proteins, transcription activation domain, DNA binding affinity, sequence specificity, coactivator binding, transcriptional activation
MeSH terms
Protein Domains, Base Sequence, DNA, Protein Binding, Transcriptional Activation, Transcription Factor RelA, NF-kappa B p50 Subunit, Protein Multimerization

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