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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...

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Autores principales: Blanden, Adam R, Yu, Xin, Blayney, Alan J, Demas, Christopher, Ha, Jeung-Hoi, Liu, Yue, Withers, Tracy, Carpizo, Darren R, Loh, Stewart N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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.
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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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