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Modulation of Global Low-Frequency Motions Underlies Allosteric Regulation: Demonstration in CRP/FNR Family Transcription Factors

Rodgers, TL; Townsend, PD; Burnell, D; Jones, ML; Richards, SA; McLeish, TCB; Pohl, E; Wilson, MR; Cann, MJ

Modulation of Global Low-Frequency Motions Underlies Allosteric Regulation: Demonstration in CRP/FNR Family Transcription Factors Thumbnail


Authors

TL Rodgers

PD Townsend

D Burnell

ML Jones

SA Richards

TCB McLeish

E Pohl



Abstract

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.

Journal Article Type Article
Publication Date Jan 1, 2013
Deposit Date Aug 13, 2013
Publicly Available Date Sep 11, 2013
Journal PLoS Biology
Print ISSN 1544-9173
Electronic ISSN 1545-7885
Publisher Public Library of Science
Peer Reviewed Peer Reviewed
Volume 11
Issue 9
Article Number e1001651
DOI https://doi.org/10.1371/journal.pbio.1001651
Public URL https://durham-repository.worktribe.com/output/1449067

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Copyright: © 2013 Rodgers et al. 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 credited.






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