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

Babel, Heiko ; Bischofs, Ilka B.

In: BMC Systems Biology, 10 (2016), Nr. 35. pp. 1-18. ISSN 1752-0509

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Download (2MB) | Lizenz: Creative Commons LizenzvertragMolecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs) by Babel, Heiko ; Bischofs, Ilka B. underlies the terms of Creative Commons Attribution 3.0 Germany

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Abstract

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 EC50 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.

Item Type: Article
Journal or Publication Title: BMC Systems Biology
Volume: 10
Number: 35
Publisher: BioMed Central
Place of Publication: London
Date Deposited: 04 May 2016 10:25
Date: 2016
ISSN: 1752-0509
Page Range: pp. 1-18
Faculties / Institutes: Service facilities > Center for Molecular Biology Heidelberg
Service facilities > Bioquant
Service facilities > Cluster of Excellence Cellular Networks
Service facilities > Graduiertenschulen > Graduiertenschule Molekulare und Zelluläre Biologie
Subjects: 570 Life sciences
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