Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.

Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dyna...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Thomas L Rodgers, Philip D Townsend, David Burnell, Matthew L Jones, Shane A Richards, Tom C B McLeish, Ehmke Pohl, Mark R Wilson, Martin J Cann
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/313384a500c94f30bfc7ec0bdb187ff3
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:313384a500c94f30bfc7ec0bdb187ff3
record_format	dspace
spelling	oai:doaj.org-article:313384a500c94f30bfc7ec0bdb187ff32021-11-18T05:37:51ZModulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.1544-91731545-788510.1371/journal.pbio.1001651https://doaj.org/article/313384a500c94f30bfc7ec0bdb187ff32013-09-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24058293/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein "design space" that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics.Thomas L RodgersPhilip D TownsendDavid BurnellMatthew L JonesShane A RichardsTom C B McLeishEhmke PohlMark R WilsonMartin J CannPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 11, Iss 9, p e1001651 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Thomas L Rodgers Philip D Townsend David Burnell Matthew L Jones Shane A Richards Tom C B McLeish Ehmke Pohl Mark R Wilson Martin J Cann Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
description	Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein "design space" that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics.
format	article
author	Thomas L Rodgers Philip D Townsend David Burnell Matthew L Jones Shane A Richards Tom C B McLeish Ehmke Pohl Mark R Wilson Martin J Cann
author_facet	Thomas L Rodgers Philip D Townsend David Burnell Matthew L Jones Shane A Richards Tom C B McLeish Ehmke Pohl Mark R Wilson Martin J Cann
author_sort	Thomas L Rodgers
title	Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
title_short	Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
title_full	Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
title_fullStr	Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
title_full_unstemmed	Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.
title_sort	modulation of global low-frequency motions underlies allosteric regulation: demonstration in crp/fnr family transcription factors.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/313384a500c94f30bfc7ec0bdb187ff3
work_keys_str_mv	AT thomaslrodgers modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT philipdtownsend modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT davidburnell modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT matthewljones modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT shanearichards modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT tomcbmcleish modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT ehmkepohl modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT markrwilson modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors AT martinjcann modulationofgloballowfrequencymotionsunderliesallostericregulationdemonstrationincrpfnrfamilytranscriptionfactors
_version_	1718424841184346112

Modulation of global low-frequency motions underlies allosteric regulation: demonstration in CRP/FNR family transcription factors.

Ejemplares similares