ArticleJournal of the American Chemical Society2017
Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- An Integrative ATAC-Seq and RNA-Seq Analysis of Spleen Tissues from Largemouth Bass (International journal of molecular sciences · 2026Article
- The VelB IDD promotes selective heterodimer formation of velvet proteins for fungal development.Life science alliance · 2026Article
- Illuminating Protein Allostery by Chemically Accurate Contact Response Analysis (ChACRA).Journal of chemical theory and computation · 2024Article
- Predicting protein conformational motions using energetic frustration analysis and AlphaFold2.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Paired yeast one-hybrid assays to detect DNA-binding cooperativity and antagonism across transcription factors.Nature communications · 2023Article
- Computationally exploring the mechanism of bacteriophage T7 gp4 helicase translocating along ssDNA.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Exploring the folding energy landscapes of heme proteins using a hybrid AWSEM-heme model.Journal of biological physics · 2022Article
- The molecular basis of allostery in a facilitated dissociation process.Structure (London, England : 1993) · 2021Article
- The N-terminal domain of RfaH plays an active role in protein fold-switching.PLoS computational biology · 2021Article
- Binding Dynamics of Disordered Linker Histone H1 with a Nucleosomal Particle.Journal of molecular biology · 2021Article
- Frustration and Direct-Coupling Analyses to Predict Formation and Function of Adeno-Associated Virus.Biophysical journal · 2021Article
- Fibril Surface-Dependent Amyloid Precursors Revealed by Coarse-Grained Molecular Dynamics Simulation.Frontiers in molecular biosciences · 2021Article
- The protection of NF-κB inhibition on kidney injury of systemic lupus erythematosus mice may be correlated with lncRNA TUG1.The Kaohsiung journal of medical sciences · 2020Article
- Mechanisms of noncanonical binding dynamics in multivalent protein-protein interactions.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Disorder Mediated Oligomerization ofThe journal of physical chemistry. B · 2019Article
- Forging tools for refining predicted protein structures.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Sliding Mechanism at a Coiled-Coil Interface.Biophysical journal · 2019Article
- Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level.Biomolecules · 2019Article
- Considering Abundance, Affinity, and Binding Site Availability in the NF-κB Target Selection Puzzle.Frontiers in immunology · 2019Review
- Tunable order-disorder continuum in protein-DNA interactions.Nucleic acids research · 2018Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Many eukaryotic transcription factors function after forming oligomers. The choice of protein partners is a nonrandom event that has distinct functional consequences for gene regulation. In the present work we examine three dimers of transcription factors in the NFκB family: p50p50, p50p65, and p65p65. The NFκB dimers bind to a myriad of genomic sites and switch the targeted genes on or off with precision. The p65p50 heterodimer of NFκB is the strongest DNA binder, and its unbinding is controlled kinetically by molecular stripping from the DNA induced by IκB. In contrast, the homodimeric forms of NFκB, p50p50 and p65p65, bind DNA with significantly less affinity, which places the DNA residence of the homodimers under thermodynamic rather than kinetic control. It seems paradoxical that the heterodimer should bind more strongly than either of the symmetric homodimers since DNA is a nearly symmetric target. Using a variety of energy landscape analysis tools, here we uncover the features in the molecular architecture of NFκB dimers that are responsible for these drastically different binding free energies. We show that frustration in the heterodimer interface gives the heterodimer greater conformational plasticity, allowing the heterodimer to better accommodate the DNA. We also show how the elastic energy and mechanical strain in NFκB dimers can be found by extracting the principal components of the fluctuations in Cartesian coordinates as well as fluctuations in the space of physical contacts, which are sampled via simulations with a predictive energy landscape Hamiltonian. These energetic contributions determine the specific detailed mechanisms of binding and stripping for both homo- and heterodimers.
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