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Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)

BACKGROUND: Rap proteins from Bacilli directly target response regulators of bacterial two-component systems and modulate their activity. Their effects are controlled by binding of signaling peptides to an allosteric site. Hence Raps exemplify a class of monomeric signaling receptors, which we call...

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Autores principales: Babel, Heiko, Bischofs, Ilka B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849100/
https://www.ncbi.nlm.nih.gov/pubmed/27122155
http://dx.doi.org/10.1186/s12918-016-0274-3
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author Babel, Heiko
Bischofs, Ilka B.
author_facet Babel, Heiko
Bischofs, Ilka B.
author_sort Babel, Heiko
collection PubMed
description BACKGROUND: Rap proteins from Bacilli directly target response regulators of bacterial two-component systems and modulate their activity. Their effects are controlled by binding of signaling peptides to an allosteric site. Hence Raps exemplify a class of monomeric signaling receptors, which we call switchable allosteric modulator proteins (SAMPs). These proteins have potential applications in diverse biomedical and biotechnical settings, but a quantitative understanding of the impact of molecular and cellular factors on signal transduction is lacking. Here we introduce mathematical models that elucidate how signals are propagated though the network upon receptor stimulation and control the level of active response regulator. RESULTS: Based on a systematic parameter analysis of the models, we show that key features of the dose-response behavior at steady state are controlled either by the molecular properties of the modulator or the signaling context. In particular, we find that the biochemical activity (i.e. non-enzymatic vs. enzymatic) and allosteric properties of the modulator control the response amplitude. The Hill coefficient and the EC(50) are controlled in addition by the relative ligand affinities. By tuning receptor properties, either graded or more switch-like (memory-less) response functions can be fashioned. Furthermore, we show that other contextual factors (e.g. relative concentrations of network components and kinase activity) have a substantial impact on the response, and we predict that there exists a modulator concentration which is optimal for response amplitude. CONCLUSION: We discuss data on Rap-Phr systems in B. subtilis to show how our models can contribute to an integrated view of SAMP signaling by combining biochemical, structural and physiological insights. Our results also suggest that SAMPs could be evolved or engineered to implement diverse response behaviors. However—without additional regulatory controls—they can generate rather variable cellular outputs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0274-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-48491002016-04-29 Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs) Babel, Heiko Bischofs, Ilka B. BMC Syst Biol Research Article BACKGROUND: Rap proteins from Bacilli directly target response regulators of bacterial two-component systems and modulate their activity. Their effects are controlled by binding of signaling peptides to an allosteric site. Hence Raps exemplify a class of monomeric signaling receptors, which we call switchable allosteric modulator proteins (SAMPs). These proteins have potential applications in diverse biomedical and biotechnical settings, but a quantitative understanding of the impact of molecular and cellular factors on signal transduction is lacking. Here we introduce mathematical models that elucidate how signals are propagated though the network upon receptor stimulation and control the level of active response regulator. RESULTS: Based on a systematic parameter analysis of the models, we show that key features of the dose-response behavior at steady state are controlled either by the molecular properties of the modulator or the signaling context. In particular, we find that the biochemical activity (i.e. non-enzymatic vs. enzymatic) and allosteric properties of the modulator control the response amplitude. The Hill coefficient and the EC(50) are controlled in addition by the relative ligand affinities. By tuning receptor properties, either graded or more switch-like (memory-less) response functions can be fashioned. Furthermore, we show that other contextual factors (e.g. relative concentrations of network components and kinase activity) have a substantial impact on the response, and we predict that there exists a modulator concentration which is optimal for response amplitude. CONCLUSION: We discuss data on Rap-Phr systems in B. subtilis to show how our models can contribute to an integrated view of SAMP signaling by combining biochemical, structural and physiological insights. Our results also suggest that SAMPs could be evolved or engineered to implement diverse response behaviors. However—without additional regulatory controls—they can generate rather variable cellular outputs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12918-016-0274-3) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-27 /pmc/articles/PMC4849100/ /pubmed/27122155 http://dx.doi.org/10.1186/s12918-016-0274-3 Text en © Babel and Bischofs. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Babel, Heiko
Bischofs, Ilka B.
Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)
title Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)
title_full Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)
title_fullStr Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)
title_full_unstemmed Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)
title_short Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs)
title_sort molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (samps)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849100/
https://www.ncbi.nlm.nih.gov/pubmed/27122155
http://dx.doi.org/10.1186/s12918-016-0274-3
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