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Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization
p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse fun...
Autores principales: | , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916859/ https://www.ncbi.nlm.nih.gov/pubmed/20700496 http://dx.doi.org/10.1371/journal.pcbi.1000878 |
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author | Pan, Yongping Nussinov, Ruth |
author_facet | Pan, Yongping Nussinov, Ruth |
author_sort | Pan, Yongping |
collection | PubMed |
description | p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects. |
format | Text |
id | pubmed-2916859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29168592010-08-10 Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization Pan, Yongping Nussinov, Ruth PLoS Comput Biol Research Article p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects. Public Library of Science 2010-08-05 /pmc/articles/PMC2916859/ /pubmed/20700496 http://dx.doi.org/10.1371/journal.pcbi.1000878 Text en Pan, Nussinov. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pan, Yongping Nussinov, Ruth Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization |
title | Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization |
title_full | Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization |
title_fullStr | Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization |
title_full_unstemmed | Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization |
title_short | Lysine120 Interactions with p53 Response Elements can Allosterically Direct p53 Organization |
title_sort | lysine120 interactions with p53 response elements can allosterically direct p53 organization |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916859/ https://www.ncbi.nlm.nih.gov/pubmed/20700496 http://dx.doi.org/10.1371/journal.pcbi.1000878 |
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