Sankhe, GD and Raja, R and Singh, DP and Bheemireddy, S and Rana, S and Athira, PJ and Dixit, NM and Saini, DK (2023) Sequestration of histidine kinases by non-cognate response regulators establishes a threshold level of stimulation for bacterial two-component signaling. In: Nature Communications, 14 (1).
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Abstract
Bacterial two-component systems (TCSs) consist of a sensor histidine kinase (HK) that perceives a specific signal, and a cognate response regulator (RR) that modulates the expression of target genes. Positive autoregulation improves TCS sensitivity to stimuli, but may trigger disproportionately large responses to weak signals, compromising bacterial fitness. Here, we combine experiments and mathematical modelling to reveal a general design that prevents such disproportionate responses: phosphorylated HKs (HK~Ps) can be sequestered by non-cognate RRs. We study five TCSs of Mycobacterium tuberculosis and find, for all of them, non-cognate RRs that show higher affinity than cognate RRs for HK~Ps. Indeed, in vitro assays show that HK~Ps preferentially bind higher affinity non-cognate RRs and get sequestered. Mathematical modelling indicates that this sequestration would introduce a ‘threshold’ stimulus strength for eliciting responses, thereby preventing responses to weak signals. Finally, we construct tunable expression systems in Mycobacterium bovis BCG to show that higher affinity non-cognate RRs suppress responses in vivo.
| Item Type: | Journal Article |
|---|---|
| Publication: | Nature Communications |
| Publisher: | Nature Research |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | bacterium; fitness; gene expression; numerical model; signaling; tuberculosis, bacterial protein; histidine; protein histidine kinase, bacterium; genetics; metabolism; signal transduction, Bacteria; Bacterial Proteins; Histidine; Histidine Kinase; Signal Transduction |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit Division of Biological Sciences > Molecular Reproduction, Development & Genetics Division of Chemical Sciences > Materials Research Centre Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering Division of Mechanical Sciences > Chemical Engineering |
| Date Deposited: | 27 Nov 2023 08:50 |
| Last Modified: | 27 Nov 2023 08:50 |
| URI: | https://eprints.iisc.ac.in/id/eprint/82873 |
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