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Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis
Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagation from the regulatory to the active site requires long-range communication, the molecular mechanism of which remains a matter of debate. A classical example for long-ra...
Autores principales: | , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775130/ https://www.ncbi.nlm.nih.gov/pubmed/19936294 http://dx.doi.org/10.1371/journal.pcbi.1000574 |
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author | Stacklies, Wolfram Xia, Fei Gräter, Frauke |
author_facet | Stacklies, Wolfram Xia, Fei Gräter, Frauke |
author_sort | Stacklies, Wolfram |
collection | PubMed |
description | Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagation from the regulatory to the active site requires long-range communication, the molecular mechanism of which remains a matter of debate. A classical example for long-range allostery is the activation of the methionine repressor MetJ, a transcription factor. Binding of its co-repressor SAM increases its affinity for DNA several-fold, but has no visible conformational effect on its DNA binding interface. Our molecular dynamics simulations indicate correlated domain motions within MetJ, and quenching of these dynamics upon SAM binding entropically favors DNA binding. From monitoring conformational fluctuations alone, it is not obvious how the presence of SAM is communicated through the largely rigid core of MetJ and how SAM thereby is able to regulate MetJ dynamics. We here directly monitored the propagation of internal forces through the MetJ structure, instead of relying on conformational changes as conventionally done. Our force distribution analysis successfully revealed the molecular network for strain propagation, which connects collective domain motions through the protein core. Parts of the network are directly affected by SAM binding, giving rise to the observed quenching of fluctuations. Our results are in good agreement with experimental data. The force distribution analysis suggests itself as a valuable tool to gain insight into the molecular function of a whole class of allosteric proteins. |
format | Text |
id | pubmed-2775130 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-27751302009-11-24 Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis Stacklies, Wolfram Xia, Fei Gräter, Frauke PLoS Comput Biol Research Article Many fundamental cellular processes such as gene expression are tightly regulated by protein allostery. Allosteric signal propagation from the regulatory to the active site requires long-range communication, the molecular mechanism of which remains a matter of debate. A classical example for long-range allostery is the activation of the methionine repressor MetJ, a transcription factor. Binding of its co-repressor SAM increases its affinity for DNA several-fold, but has no visible conformational effect on its DNA binding interface. Our molecular dynamics simulations indicate correlated domain motions within MetJ, and quenching of these dynamics upon SAM binding entropically favors DNA binding. From monitoring conformational fluctuations alone, it is not obvious how the presence of SAM is communicated through the largely rigid core of MetJ and how SAM thereby is able to regulate MetJ dynamics. We here directly monitored the propagation of internal forces through the MetJ structure, instead of relying on conformational changes as conventionally done. Our force distribution analysis successfully revealed the molecular network for strain propagation, which connects collective domain motions through the protein core. Parts of the network are directly affected by SAM binding, giving rise to the observed quenching of fluctuations. Our results are in good agreement with experimental data. The force distribution analysis suggests itself as a valuable tool to gain insight into the molecular function of a whole class of allosteric proteins. Public Library of Science 2009-11-20 /pmc/articles/PMC2775130/ /pubmed/19936294 http://dx.doi.org/10.1371/journal.pcbi.1000574 Text en Stacklies et al. 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 Stacklies, Wolfram Xia, Fei Gräter, Frauke Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis |
title | Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis |
title_full | Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis |
title_fullStr | Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis |
title_full_unstemmed | Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis |
title_short | Dynamic Allostery in the Methionine Repressor Revealed by Force Distribution Analysis |
title_sort | dynamic allostery in the methionine repressor revealed by force distribution analysis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775130/ https://www.ncbi.nlm.nih.gov/pubmed/19936294 http://dx.doi.org/10.1371/journal.pcbi.1000574 |
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