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Solution structure and binding specificity of the p63 DNA binding domain

p63 is a close homologue of p53 and, together with p73, is grouped into the p53 family of transcription factors. p63 is known to be involved in the induction of controlled apoptosis important for differentiation processes, germ line integrity and development. Despite its high homology to p53, especi...

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Autores principales: Enthart, Andreas, Klein, Christian, Dehner, Alexander, Coles, Murray, Gemmecker, Gerd, Kessler, Horst, Hagn, Franz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880913/
https://www.ncbi.nlm.nih.gov/pubmed/27225672
http://dx.doi.org/10.1038/srep26707
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author Enthart, Andreas
Klein, Christian
Dehner, Alexander
Coles, Murray
Gemmecker, Gerd
Kessler, Horst
Hagn, Franz
author_facet Enthart, Andreas
Klein, Christian
Dehner, Alexander
Coles, Murray
Gemmecker, Gerd
Kessler, Horst
Hagn, Franz
author_sort Enthart, Andreas
collection PubMed
description p63 is a close homologue of p53 and, together with p73, is grouped into the p53 family of transcription factors. p63 is known to be involved in the induction of controlled apoptosis important for differentiation processes, germ line integrity and development. Despite its high homology to p53, especially within the DNA binding domain (DBD), p63-DBD does not show cooperative DNA binding properties and is significantly more stable against thermal and chemical denaturation. Here, we determined the solution structure of p63-DBD and show that it is markedly less dynamic than p53-DBD. In addition, we also investigate the effect of a double salt bridge present in p53-DBD, but not in p63-DBD on the cooperative binding behavior and specificity to various DNA sites. Restoration of the salt bridges in p63-DBD by mutagenesis leads to enhanced binding affinity to p53-specific, but not p63-specific response elements. Furthermore, we show that p63-DBD is capable of binding to anti-apoptotic BclxL via its DNA binding interface, a feature that has only been shown for p53 so far. These data suggest that all p53 family members - despite alterations in the specificity and binding affinity - are capable of activating pro-apoptotic pathways in a tissue specific manner.
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spelling pubmed-48809132016-06-07 Solution structure and binding specificity of the p63 DNA binding domain Enthart, Andreas Klein, Christian Dehner, Alexander Coles, Murray Gemmecker, Gerd Kessler, Horst Hagn, Franz Sci Rep Article p63 is a close homologue of p53 and, together with p73, is grouped into the p53 family of transcription factors. p63 is known to be involved in the induction of controlled apoptosis important for differentiation processes, germ line integrity and development. Despite its high homology to p53, especially within the DNA binding domain (DBD), p63-DBD does not show cooperative DNA binding properties and is significantly more stable against thermal and chemical denaturation. Here, we determined the solution structure of p63-DBD and show that it is markedly less dynamic than p53-DBD. In addition, we also investigate the effect of a double salt bridge present in p53-DBD, but not in p63-DBD on the cooperative binding behavior and specificity to various DNA sites. Restoration of the salt bridges in p63-DBD by mutagenesis leads to enhanced binding affinity to p53-specific, but not p63-specific response elements. Furthermore, we show that p63-DBD is capable of binding to anti-apoptotic BclxL via its DNA binding interface, a feature that has only been shown for p53 so far. These data suggest that all p53 family members - despite alterations in the specificity and binding affinity - are capable of activating pro-apoptotic pathways in a tissue specific manner. Nature Publishing Group 2016-05-26 /pmc/articles/PMC4880913/ /pubmed/27225672 http://dx.doi.org/10.1038/srep26707 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Enthart, Andreas
Klein, Christian
Dehner, Alexander
Coles, Murray
Gemmecker, Gerd
Kessler, Horst
Hagn, Franz
Solution structure and binding specificity of the p63 DNA binding domain
title Solution structure and binding specificity of the p63 DNA binding domain
title_full Solution structure and binding specificity of the p63 DNA binding domain
title_fullStr Solution structure and binding specificity of the p63 DNA binding domain
title_full_unstemmed Solution structure and binding specificity of the p63 DNA binding domain
title_short Solution structure and binding specificity of the p63 DNA binding domain
title_sort solution structure and binding specificity of the p63 dna binding domain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880913/
https://www.ncbi.nlm.nih.gov/pubmed/27225672
http://dx.doi.org/10.1038/srep26707
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