ArticleJournal of molecular biology2021
Cancer-Associated Mutations Perturb the Disordered Ensemble and Interactions of the Intrinsically Disordered p53 Transactivation Domain.
Article in Journal of molecular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 25 citations in OpenAlex.
- How protein hydration depends on amino acid composition, peptide conformation, and force fields.Biophysical journal · 2026Article
- Pathogenic Proteins Through the Lens of NMR Spectroscopy: Structural and Functional Insights into Disease.Cell biochemistry and biophysics · 2025Review
- A phase transition modulates the protective function of a tardigrade disordered protein during desiccation.Protein science : a publication of the Protein Society · 2025Article
- Article
- Single-point mutations in disordered proteins: Linking sequence, ensemble, and function.Current opinion in structural biology · 2025Review
- Likely Overstabilization of Charge-Charge Interactions in CHARMM36m(w): A Case for a99SB-disp Water.The journal of physical chemistry. B · 2024Article
- Exploring the dynamics and interactions of the N-myc transactivation domain through solution nuclear magnetic resonance spectroscopy.The Biochemical journal · 2024Article
- Structural biases in disordered proteins are prevalent in the cell.Nature structural & molecular biology · 2024Article
- Molecular simulations integrated with experiments for probing the interaction dynamics and binding mechanisms of intrinsically disordered proteins.Current opinion in structural biology · 2024Review
- Characterization of Intrinsically Disordered Proteins in Healthy and Diseased States by Nuclear Magnetic Resonance.Reviews on recent clinical trials · 2024Review
- Intrinsically disordered proteins and conformational noise: The hypothesis a decade later.iScience · 2023Review
- Machine Learning Generation of Dynamic Protein Conformational Ensembles.Molecules (Basel, Switzerland) · 2023Review
- Re-Balancing Replica Exchange with Solute Tempering for Sampling Dynamic Protein Conformations.Journal of chemical theory and computation · 2023Article
- Toward Accurate Coarse-Grained Simulations of Disordered Proteins and Their Dynamic Interactions.Journal of chemical information and modeling · 2022Article
- Peptide and protein chemistry approaches to study the tumor suppressor protein p53.Organic & biomolecular chemistry · 2022Review
- Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions.Biomolecules · 2021Review
- Matrin3: Disorder and ALS Pathogenesis.Frontiers in molecular biosciences · 2021Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Intrinsically disordered proteins (IDPs) are key components of regulatory networks that control crucial aspects of cell decision making. The intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 mediates its interactions with multiple regulatory pathways to control the p53 homeostasis during the cellular response to genotoxic stress. Many cancer-associated mutations have been discovered in p53-TAD, but their structural and functional consequences are poorly understood. Here, by combining atomistic simulations, NMR spectroscopy, and binding assays, we demonstrate that cancer-associated mutations can significantly perturb the balance of p53 interactions with key activation and degradation regulators. Importantly, the four mutations studied in this work do not all directly disrupt the known interaction interfaces. Instead, at least three of these mutations likely modulate the disordered state of p53-TAD to perturb its interactions with regulators. Specifically, NMR and simulation analysis together suggest that these mutations can modulate the level of conformational expansion as well as rigidity of the disordered state. Our work suggests that the disordered conformational ensemble of p53-TAD can serve as a central conduit in regulating the response to various cellular stimuli at the protein-protein interaction level. Understanding how the disordered state of IDPs may be modulated by regulatory signals and/or disease associated perturbations will be essential in the studies on the role of IDPs in biology and diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.