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

Babel, H., & Bischofs, I. B. (2016). Molecular and cellular factors control signal transduction via switchable allosteric modulator proteins (SAMPs). BMC SYSTEMS BIOLOGY, 10: 35. doi:10.1186/s12918-016-0274-3.

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 Creators:
Babel, Heiko1, Author
Bischofs, Ilka B.2, Author                 
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1external, ou_persistent22              
2Center for Molecular Biology (ZMBH) and Center for the Quantitative Analysis of Molecular and Cellular Biosystems (BioQuant), University of Heidelberg, Germany, ou_persistent22              

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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.

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 Dates: 2016
 Publication Status: Published online
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 Identifiers: ISI: 000375100100001
DOI: 10.1186/s12918-016-0274-3
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Title: BMC SYSTEMS BIOLOGY
Source Genre: Journal
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Pages: - Volume / Issue: 10 Sequence Number: 35 Start / End Page: - Identifier: ISSN: 1752-0509