ArticleProceedings of the National Academy of Sciences of the United States of America2015
Mechanism of initiation of aggregation of p53 revealed by Φ-value analysis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- Cancer-linked aggregation of p53 is driven by sequence-encoded frustration, solvation, and hydrophobic gating absent in its paralogs.Communications chemistry · 2026Article
- Mesoscopic p53-rich clusters represent a new class of protein condensates.Biophysics reviews · 2025Review
- p53 amyloid pathology is correlated with higher cancer grade irrespective of the mutant or wild-type form.Journal of cell science · 2023Article
- Targeting mutant p53 stabilization for cancer therapy.Frontiers in pharmacology · 2023Review
- Characterization of full-length p53 aggregates and their kinetics of formation.Biophysical journal · 2022Article
- Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding.Molecules (Basel, Switzerland) · 2022Article
- High-throughput functional evaluation of human cancer-associated mutations using base editors.Nature biotechnology · 2022Article
- p53, A Victim of the Prion Fashion.Cancers · 2021Review
- Liquid-like droplet formation by tumor suppressor p53 induced by multivalent electrostatic interactions between two disordered domains.Scientific reports · 2020Article
- Salvation of the fallen angel: Reactivating mutant p53.British journal of pharmacology · 2019Review
- Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket.Nucleic acids research · 2019Article
- Probing the Occurrence of Soluble Oligomers through Amyloid Aggregation Scaling Laws.Biomolecules · 2018Article
- Aggregation-primed molten globule conformers of the p53 core domain provide potential tools for studying p53C aggregation in cancer.The Journal of biological chemistry · 2018Article
- Distinct modulatory role of RNA in the aggregation of the tumor suppressor protein p53 core domain.The Journal of biological chemistry · 2017Article
- Multisite aggregation of p53 and implications for drug rescue.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- The p53 tetramer shows an induced-fit interaction of the C-terminal domain with the DNA-binding domain.Oncogene · 2016Article
- Self-aggregation and coaggregation of the p53 core fragment with its aggregation gatekeeper variant.Physical chemistry chemical physics : PCCP · 2016Article
- Cancer associated missense mutations in BAP1 catalytic domain induce amyloidogenic aggregation: A new insight in enzymatic inactivation.Scientific reports · 2015Article
- Propagation of aggregated p53: Cross-reaction and coaggregation vs. seeding.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Misfolding, Aggregation, and Disordered Segments in c-Abl and p53 in Human Cancer.Frontiers in oncology · 2015Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Many oncogenic mutations inactivate the tumor suppressor p53 by destabilizing it, leading to its rapid aggregation. Small molecule drugs are being developed to stabilize such mutants. The kinetics of aggregation of p53 is deceptively simple. The initial steps in the micromolar concentration range follow apparent sigmoidal sequential first-order kinetics, with rate constants k1 and k2. However, the aggregation kinetics of a panel of mutants prepared for Φ-value analysis has now revealed a bimolecular reaction hidden beneath the observed first-order kinetics. Φu measures the degree of local unfolding on a scale of 0-1. A number of sequential Φu-values of ∼1 for k1 and k2 over the molecule implied more than one protein molecule must be reacting, which was confirmed by finding a clear concentration dependence at submicromolar protein. Numerical simulations showed that the kinetics of the more complex mechanism is difficult, if not impossible, to distinguish experimentally from simple first order under many reaction conditions. Stabilization of mutants by small molecules will be enhanced because they decrease both k1 and k2. The regions with high Φu-values point to the areas where stabilization of mutant proteins would have the greatest effect.
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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.