Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants
- SUNY Upstate Medical University, United States
- Rutgers Cancer Institute of New Jersey, United States
- University of Rochester Medical Center, United States
Abstract
Missense mutations in the p53 DNA binding domain (DBD) contribute to half of new cancer cases annually. Here we present a thermodynamic model that quantifies and links the major pathways by which mutations inactivate p53. We find that DBD possesses two unusual properties-one of the highest zinc affinities of any eukaryotic protein and extreme instability in the absence of zinc-which are predicted to poise p53 on the cusp of folding/unfolding in the cell, with a major determinant being available zinc concentration. We analyze the 20 most common tumorigenic p53 mutations and find that 80% impair zinc affinity, thermodynamic stability, or both. Biophysical, cell-based, and murine xenograft experiments demonstrate that a synthetic zinc metallochaperone rescues not only mutations that decrease zinc affinity, but also mutations that destabilize DBD without impairing zinc binding. The results suggest that zinc metallochaperones have the capability to treat 120,500 patients annually in the U.S.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Author details
Funding
National Institutes of Health (F30 GM113299)
- Adam R Blanden
- Stewart N Loh
National Institutes of Health (R01 CA200800)
- Darren R Carpizo
National Institutes of Health (K08 CA172676)
- Darren R Carpizo
Breast Cancer Research Foundation
- Darren R Carpizo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were housed and treated according to guidelines established by the Institutional Animal Care and Use Committee of Rutgers University, who also approved all mouse experiments. (animal protocol PROTO99900044, approval date 10/16/2019 - 10/15/2022).
Copyright
© 2020, Blanden et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants
eLife 9:e61487.
https://doi.org/10.7554/eLife.61487
