Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.

<h4>Background</h4>The protein p53 plays an active role in the regulation of cell cycle. In about half of human cancers, the protein is inactivated by mutations located primarily in its DNA-binding domain. Interestingly, a number of these mutations possess temperature-induced DNA-binding...

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Autores principales:	Khaled Barakat, Bilkiss B Issack, Maria Stepanova, Jack Tuszynski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/02282b8e3a5848b99b7a0169ecd7d76f
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spelling	oai:doaj.org-article:02282b8e3a5848b99b7a0169ecd7d76f2021-11-18T07:34:09ZEffects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.1932-620310.1371/journal.pone.0027651https://doaj.org/article/02282b8e3a5848b99b7a0169ecd7d76f2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22110706/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The protein p53 plays an active role in the regulation of cell cycle. In about half of human cancers, the protein is inactivated by mutations located primarily in its DNA-binding domain. Interestingly, a number of these mutations possess temperature-induced DNA-binding characteristics. A striking example is the mutation of Arg248 into glutamine or tryptophan. These mutants are defective for binding to DNA at 310 K although they have been shown to bind specifically to several p53 response elements at sub-physiological temperatures (298-306 K).<h4>Methodology/principal findings</h4>This important experimental finding motivated us to examine the effects of temperature on the structure and configuration of R248Q mutant and compare it to the wild type protein. Our aim is to determine how and where structural changes of mutant variants take place due to temperature changes. To answer these questions, we compared the mutant to the wild-type proteins from two different aspects. First, we investigated the systems at the atomistic level through their DNA-binding affinity, hydrogen bond networks and spatial distribution of water molecules. Next, we assessed changes in their long-lived conformational motions at the coarse-grained level through the collective dynamics of their side-chain and backbone atoms separately.<h4>Conclusions</h4>The experimentally observed effect of temperature on the DNA-binding properties of p53 is reproduced. Analysis of atomistic and coarse-grained data reveal that changes in binding are determined by a few key residues and provide a rationale for the mutant-loss of binding at physiological temperatures. The findings can potentially enable a rescue strategy for the mutant structure.Khaled BarakatBilkiss B IssackMaria StepanovaJack TuszynskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 11, p e27651 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Khaled Barakat Bilkiss B Issack Maria Stepanova Jack Tuszynski Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.
description	<h4>Background</h4>The protein p53 plays an active role in the regulation of cell cycle. In about half of human cancers, the protein is inactivated by mutations located primarily in its DNA-binding domain. Interestingly, a number of these mutations possess temperature-induced DNA-binding characteristics. A striking example is the mutation of Arg248 into glutamine or tryptophan. These mutants are defective for binding to DNA at 310 K although they have been shown to bind specifically to several p53 response elements at sub-physiological temperatures (298-306 K).<h4>Methodology/principal findings</h4>This important experimental finding motivated us to examine the effects of temperature on the structure and configuration of R248Q mutant and compare it to the wild type protein. Our aim is to determine how and where structural changes of mutant variants take place due to temperature changes. To answer these questions, we compared the mutant to the wild-type proteins from two different aspects. First, we investigated the systems at the atomistic level through their DNA-binding affinity, hydrogen bond networks and spatial distribution of water molecules. Next, we assessed changes in their long-lived conformational motions at the coarse-grained level through the collective dynamics of their side-chain and backbone atoms separately.<h4>Conclusions</h4>The experimentally observed effect of temperature on the DNA-binding properties of p53 is reproduced. Analysis of atomistic and coarse-grained data reveal that changes in binding are determined by a few key residues and provide a rationale for the mutant-loss of binding at physiological temperatures. The findings can potentially enable a rescue strategy for the mutant structure.
format	article
author	Khaled Barakat Bilkiss B Issack Maria Stepanova Jack Tuszynski
author_facet	Khaled Barakat Bilkiss B Issack Maria Stepanova Jack Tuszynski
author_sort	Khaled Barakat
title	Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.
title_short	Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.
title_full	Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.
title_fullStr	Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.
title_full_unstemmed	Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.
title_sort	effects of temperature on the p53-dna binding interactions and their dynamical behavior: comparing the wild type to the r248q mutant.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/02282b8e3a5848b99b7a0169ecd7d76f
work_keys_str_mv	AT khaledbarakat effectsoftemperatureonthep53dnabindinginteractionsandtheirdynamicalbehaviorcomparingthewildtypetother248qmutant AT bilkissbissack effectsoftemperatureonthep53dnabindinginteractionsandtheirdynamicalbehaviorcomparingthewildtypetother248qmutant AT mariastepanova effectsoftemperatureonthep53dnabindinginteractionsandtheirdynamicalbehaviorcomparingthewildtypetother248qmutant AT jacktuszynski effectsoftemperatureonthep53dnabindinginteractionsandtheirdynamicalbehaviorcomparingthewildtypetother248qmutant
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Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: comparing the wild type to the R248Q mutant.

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