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Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants
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 affi...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728444/ https://www.ncbi.nlm.nih.gov/pubmed/33263541 http://dx.doi.org/10.7554/eLife.61487 |
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author | Blanden, Adam R Yu, Xin Blayney, Alan J Demas, Christopher Ha, Jeung-Hoi Liu, Yue Withers, Tracy Carpizo, Darren R Loh, Stewart N |
author_facet | Blanden, Adam R Yu, Xin Blayney, Alan J Demas, Christopher Ha, Jeung-Hoi Liu, Yue Withers, Tracy Carpizo, Darren R Loh, Stewart N |
author_sort | Blanden, Adam R |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7728444 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-77284442020-12-14 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 eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2020-12-02 /pmc/articles/PMC7728444/ /pubmed/33263541 http://dx.doi.org/10.7554/eLife.61487 Text en © 2020, Blanden et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Blanden, Adam R Yu, Xin Blayney, Alan J Demas, Christopher Ha, Jeung-Hoi Liu, Yue Withers, Tracy Carpizo, Darren R Loh, Stewart N Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
title | Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
title_full | Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
title_fullStr | Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
title_full_unstemmed | Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
title_short | Zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
title_sort | zinc shapes the folding landscape of p53 and establishes a pathway for reactivating structurally diverse cancer mutants |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728444/ https://www.ncbi.nlm.nih.gov/pubmed/33263541 http://dx.doi.org/10.7554/eLife.61487 |
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