Phosphate sink containing two-component signaling systems as tunable threshold devices

Research output: Contribution to journalJournal articleResearchpeer-review

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Phosphate sink containing two-component signaling systems as tunable threshold devices. / Amin, Munia; Kothamachu, Varun B; Feliu, Elisenda; Scharf, Birgit E; Porter, Steven L; Soyer, Orkun S.

In: PLoS Computational Biology, Vol. 10, No. 10, 10.2014, p. e1003890.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Amin, M, Kothamachu, VB, Feliu, E, Scharf, BE, Porter, SL & Soyer, OS 2014, 'Phosphate sink containing two-component signaling systems as tunable threshold devices', PLoS Computational Biology, vol. 10, no. 10, pp. e1003890. https://doi.org/10.1371/journal.pcbi.1003890

APA

Amin, M., Kothamachu, V. B., Feliu, E., Scharf, B. E., Porter, S. L., & Soyer, O. S. (2014). Phosphate sink containing two-component signaling systems as tunable threshold devices. PLoS Computational Biology, 10(10), e1003890. https://doi.org/10.1371/journal.pcbi.1003890

Vancouver

Amin M, Kothamachu VB, Feliu E, Scharf BE, Porter SL, Soyer OS. Phosphate sink containing two-component signaling systems as tunable threshold devices. PLoS Computational Biology. 2014 Oct;10(10):e1003890. https://doi.org/10.1371/journal.pcbi.1003890

Author

Amin, Munia ; Kothamachu, Varun B ; Feliu, Elisenda ; Scharf, Birgit E ; Porter, Steven L ; Soyer, Orkun S. / Phosphate sink containing two-component signaling systems as tunable threshold devices. In: PLoS Computational Biology. 2014 ; Vol. 10, No. 10. pp. e1003890.

Bibtex

@article{634ece7c720545ce8ece187121fcb198,
title = "Phosphate sink containing two-component signaling systems as tunable threshold devices",
abstract = "Synthetic biology aims to design de novo biological systems and reengineer existing ones. These efforts have mostly focused on transcriptional circuits, with reengineering of signaling circuits hampered by limited understanding of their systems dynamics and experimental challenges. Bacterial two-component signaling systems offer a rich diversity of sensory systems that are built around a core phosphotransfer reaction between histidine kinases and their output response regulator proteins, and thus are a good target for reengineering through synthetic biology. Here, we explore the signal-response relationship arising from a specific motif found in two-component signaling. In this motif, a single histidine kinase (HK) phosphotransfers reversibly to two separate output response regulator (RR) proteins. We show that, under the experimentally observed parameters from bacteria and yeast, this motif not only allows rapid signal termination, whereby one of the RRs acts as a phosphate sink towards the other RR (i.e. the output RR), but also implements a sigmoidal signal-response relationship. We identify two mathematical conditions on system parameters that are necessary for sigmoidal signal-response relationships and define key parameters that control threshold levels and sensitivity of the signal-response curve. We confirm these findings experimentally, by in vitro reconstitution of the one HK-two RR motif found in the Sinorhizobium meliloti chemotaxis pathway and measuring the resulting signal-response curve. We find that the level of sigmoidality in this system can be experimentally controlled by the presence of the sink RR, and also through an auxiliary protein that is shown to bind to the HK (yielding Hill coefficients of above 7). These findings show that the one HK-two RR motif allows bacteria and yeast to implement tunable switch-like signal processing and provides an ideal basis for developing threshold devices for synthetic biology applications.",
author = "Munia Amin and Kothamachu, {Varun B} and Elisenda Feliu and Scharf, {Birgit E} and Porter, {Steven L} and Soyer, {Orkun S}",
year = "2014",
month = oct,
doi = "10.1371/journal.pcbi.1003890",
language = "English",
volume = "10",
pages = "e1003890",
journal = "P L o S Computational Biology (Online)",
issn = "1553-7358",
publisher = "Public Library of Science",
number = "10",

}

RIS

TY - JOUR

T1 - Phosphate sink containing two-component signaling systems as tunable threshold devices

AU - Amin, Munia

AU - Kothamachu, Varun B

AU - Feliu, Elisenda

AU - Scharf, Birgit E

AU - Porter, Steven L

AU - Soyer, Orkun S

PY - 2014/10

Y1 - 2014/10

N2 - Synthetic biology aims to design de novo biological systems and reengineer existing ones. These efforts have mostly focused on transcriptional circuits, with reengineering of signaling circuits hampered by limited understanding of their systems dynamics and experimental challenges. Bacterial two-component signaling systems offer a rich diversity of sensory systems that are built around a core phosphotransfer reaction between histidine kinases and their output response regulator proteins, and thus are a good target for reengineering through synthetic biology. Here, we explore the signal-response relationship arising from a specific motif found in two-component signaling. In this motif, a single histidine kinase (HK) phosphotransfers reversibly to two separate output response regulator (RR) proteins. We show that, under the experimentally observed parameters from bacteria and yeast, this motif not only allows rapid signal termination, whereby one of the RRs acts as a phosphate sink towards the other RR (i.e. the output RR), but also implements a sigmoidal signal-response relationship. We identify two mathematical conditions on system parameters that are necessary for sigmoidal signal-response relationships and define key parameters that control threshold levels and sensitivity of the signal-response curve. We confirm these findings experimentally, by in vitro reconstitution of the one HK-two RR motif found in the Sinorhizobium meliloti chemotaxis pathway and measuring the resulting signal-response curve. We find that the level of sigmoidality in this system can be experimentally controlled by the presence of the sink RR, and also through an auxiliary protein that is shown to bind to the HK (yielding Hill coefficients of above 7). These findings show that the one HK-two RR motif allows bacteria and yeast to implement tunable switch-like signal processing and provides an ideal basis for developing threshold devices for synthetic biology applications.

AB - Synthetic biology aims to design de novo biological systems and reengineer existing ones. These efforts have mostly focused on transcriptional circuits, with reengineering of signaling circuits hampered by limited understanding of their systems dynamics and experimental challenges. Bacterial two-component signaling systems offer a rich diversity of sensory systems that are built around a core phosphotransfer reaction between histidine kinases and their output response regulator proteins, and thus are a good target for reengineering through synthetic biology. Here, we explore the signal-response relationship arising from a specific motif found in two-component signaling. In this motif, a single histidine kinase (HK) phosphotransfers reversibly to two separate output response regulator (RR) proteins. We show that, under the experimentally observed parameters from bacteria and yeast, this motif not only allows rapid signal termination, whereby one of the RRs acts as a phosphate sink towards the other RR (i.e. the output RR), but also implements a sigmoidal signal-response relationship. We identify two mathematical conditions on system parameters that are necessary for sigmoidal signal-response relationships and define key parameters that control threshold levels and sensitivity of the signal-response curve. We confirm these findings experimentally, by in vitro reconstitution of the one HK-two RR motif found in the Sinorhizobium meliloti chemotaxis pathway and measuring the resulting signal-response curve. We find that the level of sigmoidality in this system can be experimentally controlled by the presence of the sink RR, and also through an auxiliary protein that is shown to bind to the HK (yielding Hill coefficients of above 7). These findings show that the one HK-two RR motif allows bacteria and yeast to implement tunable switch-like signal processing and provides an ideal basis for developing threshold devices for synthetic biology applications.

U2 - 10.1371/journal.pcbi.1003890

DO - 10.1371/journal.pcbi.1003890

M3 - Journal article

C2 - 25357192

VL - 10

SP - e1003890

JO - P L o S Computational Biology (Online)

JF - P L o S Computational Biology (Online)

SN - 1553-7358

IS - 10

ER -

ID: 127452764