1. Cancer Biology
  2. Structural Biology and Molecular Biophysics
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Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants

  1. Adam R Blanden
  2. Xin Yu
  3. Alan J Blayney
  4. Christopher Demas
  5. Jeung-Hoi Ha
  6. Yue Liu
  7. Tracy Withers
  8. Darren R Carpizo  Is a corresponding author
  9. Stewart N Loh  Is a corresponding author
  1. SUNY Upstate Medical University, United States
  2. Rutgers Cancer Institute of New Jersey, United States
  3. University of Rochester Medical Center, United States
Research Article
  • Cited 5
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Cite this article as: eLife 2020;9:e61487 doi: 10.7554/eLife.61487

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Adam R Blanden

    Neurology, SUNY Upstate Medical University, Syracuse, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xin Yu

    Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alan J Blayney

    Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0741-1550
  4. Christopher Demas

    Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jeung-Hoi Ha

    Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yue Liu

    Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tracy Withers

    Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Darren R Carpizo

    Surgery, University of Rochester Medical Center, Rochester, United States
    For correspondence
    darren_carpizo@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
  9. Stewart N Loh

    Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, United States
    For correspondence
    lohs@upstate.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4387-9644

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).

Reviewing Editor

  1. Sarel Jacob Fleishman, Weizmann Institute of Science, Israel

Publication history

  1. Received: July 27, 2020
  2. Accepted: November 19, 2020
  3. Accepted Manuscript published: December 2, 2020 (version 1)
  4. Version of Record published: December 10, 2020 (version 2)

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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