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Cited by 78

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Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants

Blanden, Adam R, Yu, Xin, Blayney, Alan J, Demas, Christopher, Ha, Jeung-Hoi, Liu, Yue, Withers, Tracy, Carpizo, Darren R, Loh, Stewart N·2020·eLife
DOI 10.7554/elife.61487

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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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Metadata

Authors
Blanden, A. R., Yu, X., Blayney, A. J., Demas, C., Ha, J.-H., Liu, Y., Withers, T., Carpizo, D. R., & Loh, S. N.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-12-02
Volume
9
ISSN
2050-084X
DOI
10.7554/elife.61487
Cited by
78
References
2
Language
en
Licence
Funders
  • National Institutes of Health (F30 GM113299, R01 CA200800, K08 CA172676)
  • Breast Cancer Research Foundation

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CoChat. (2026). Citation check: Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants. https://app.cochat.ai/papers/10.7554/elife.61487
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Blanden, A. R., Yu, X., Blayney, A. J., Demas, C., Ha, J.-H., Liu, Y., Withers, T., Carpizo, D. R., & Loh, S. N. (2020). Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants. eLife. https://doi.org/10.7554/elife.61487

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