ArticleThe Journal of biological chemistry2018
Aggregation-primed molten globule conformers of the p53 core domain provide potential tools for studying p53C aggregation in cancer.
Article in The Journal of biological chemistry, 2018. 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, 41 citations in OpenAlex.
- Distinct Molten-Globule Conformations in an Interacting Protein Domain Resolved byAngewandte Chemie (International ed. in English) · 2026Article
- Liquid-liquid phase separation and the formation of amyloid fibrils from DcpS scavenger enzymes.Scientific reports · 2026Article
- Cancer-linked aggregation of p53 is driven by sequence-encoded frustration, solvation, and hydrophobic gating absent in its paralogs.Communications chemistry · 2026Article
- Review
- Potential enhancement of post-stroke angiogenic response by targeting the oligomeric aggregation of p53 protein.Frontiers in cellular neuroscience · 2023Review
- 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
- Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L.International journal of molecular sciences · 2022Article
- Relevance of Amorphous and Amyloid-Like Aggregates of the p53 Core Domain to Loss of its DNA-Binding Activity.Frontiers in molecular biosciences · 2022Article
- Protein of a thousand faces: The tumor-suppressive and oncogenic responses of p53.Frontiers in molecular biosciences · 2022Review
- High-resolution analysis of the conformational transition of pro-apoptotic Bak at the lipid membrane.The EMBO journal · 2021Article
- Phase separation of p53 precedes aggregation and is affected by oncogenic mutations and ligands.Chemical science · 2021Article
- Emerging Roles of Liquid-Liquid Phase Separation in Cancer: From Protein Aggregation to Immune-Associated Signaling.Frontiers in cell and developmental biology · 2021Review
- The Status of p53 Oligomeric and Aggregation States in Cancer.Biomolecules · 2020Review
- Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers.iScience · 2020Article
- Liquid-like droplet formation by tumor suppressor p53 induced by multivalent electrostatic interactions between two disordered domains.Scientific reports · 2020Article
- Loss of the p53 transactivation domain results in high amyloid aggregation of the Δ40p53 isoform in endometrial carcinoma cells.The Journal of biological chemistry · 2019Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
The functionality of the tumor suppressor p53 is altered in more than 50% of human cancers, and many individuals with cancer exhibit amyloid-like buildups of aggregated p53. An understanding of what triggers the pathogenic amyloid conversion of p53 is required for the further development of cancer therapies. Here, perturbation of the p53 core domain (p53C) with subdenaturing concentrations of guanidine hydrochloride and high hydrostatic pressure revealed native-like molten globule (MG) states, a subset of which were highly prone to amyloidogenic aggregation. We found that MG conformers of p53C, probably representing population-weighted averages of multiple states, have different volumetric properties, as determined by pressure perturbation and size-exclusion chromatography. We also found that they bind the fluorescent dye 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) and have a native-like tertiary structure that occludes the single Trp residue in p53. Fluorescence experiments revealed conformational changes of the single Trp and Tyr residues before p53 unfolding and the presence of MG conformers, some of which were highly prone to aggregation. p53C exhibited marginal unfolding cooperativity, which could be modulated from unfolding to aggregation pathways with chemical or physical forces. We conclude that trapping amyloid precursor states in solution is a promising approach for understanding p53 aggregation in cancer. Our findings support the use of single-Trp fluorescence as a probe for evaluating p53 stability, effects of mutations, and the efficacy of therapeutics designed to stabilize p53.
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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.