%0 Journal Article %1 Tindall2010Modeling %A Tindall, Marcus J. %A Porter, Steven L. %A Maini, Philip K. %A Armitage, Judith P. %D 2010 %I Public Library of Science %J PLoS Comput Biol %K chemotaxis %N 8 %P e1000896+ %R 10.1371/journal.pcbi.1000896 %T Modeling Chemotaxis Reveals the Role of Reversed Phosphotransfer and a Bi-Functional Kinase-Phosphatase %U http://dx.doi.org/10.1371/journal.pcbi.1000896 %V 6 %X Understanding how multiple signals are integrated in living cells to produce a balanced response is a major challenge in biology. Two-component signal transduction pathways, such as bacterial chemotaxis, comprise histidine protein kinases (HPKs) and response regulators (RRs). These are used to sense and respond to changes in the environment. Rhodobacter sphaeroides has a complex chemosensory network with two signaling clusters, each containing a HPK, CheA. Here we demonstrate, using a mathematical model, how the outputs of the two signaling clusters may be integrated. We use our mathematical model supported by experimental data to predict that: (1) the main RR controlling flagellar rotation, CheY6, aided by its specific phosphatase, the bifunctional kinase CheA3, acts as a phosphate sink for the other RRs; and (2) a phosphorelay pathway involving CheB2 connects the cytoplasmic cluster kinase CheA3 with the polar localised kinase CheA2, and allows CheA3-P to phosphorylate non-cognate chemotaxis RRs. These two mechanisms enable the bifunctional kinase/phosphatase activity of CheA3 to integrate and tune the sensory output of each signaling cluster to produce a balanced response. The signal integration mechanisms identified here may be widely used by other bacteria, since like R. sphaeroides, over 50\% of chemotactic bacteria have multiple cheA homologues and need to integrate signals from different sources. Chemotactic bacteria sense nutrient gradients and swim towards better environments for growth. A cluster of receptors in the cell membrane detects nutrient levels and signals via a cytoplasmic signaling pathway to the flagellum. The complexity of this signaling pathway varies across different bacterial species. The relatively simple pathway used by Escherichia coli is well understood; however, many bacteria, for example Rhodobacter sphaeroides, have more sophisticated pathways that, as well as being able to detect nutrients, are also able to assess the metabolic state of the cell. The receptors that detect metabolic state are located within an additional cluster that is physically distinct from the one that senses nutrients. In this work, we use a combination of experimentation and mathematical modeling to gain insight into the complex decision-making mechanisms that enable bacteria to weigh-up different stimuli and decide upon an appropriate response. We find novel communication mechanisms between the two signaling clusters that allow the outputs of the signaling pathways to be balanced and tuned according to the prevailing environmental conditions. The signaling principles identified here are likely to be used in other complex sensory networks.

@article{Tindall2010Modeling, abstract = {Understanding how multiple signals are integrated in living cells to produce a balanced response is a major challenge in biology. Two-component signal transduction pathways, such as bacterial chemotaxis, comprise histidine protein kinases ({HPKs}) and response regulators ({RRs}). These are used to sense and respond to changes in the environment. Rhodobacter sphaeroides has a complex chemosensory network with two signaling clusters, each containing a {HPK}, {CheA}. Here we demonstrate, using a mathematical model, how the outputs of the two signaling clusters may be integrated. We use our mathematical model supported by experimental data to predict that: (1) the main {RR} controlling flagellar rotation, {CheY6}, aided by its specific phosphatase, the bifunctional kinase {CheA3}, acts as a phosphate sink for the other {RRs}; and (2) a phosphorelay pathway involving {CheB2} connects the cytoplasmic cluster kinase {CheA3} with the polar localised kinase {CheA2}, and allows {CheA3}-P to phosphorylate non-cognate chemotaxis {RRs}. These two mechanisms enable the bifunctional kinase/phosphatase activity of {CheA3} to integrate and tune the sensory output of each signaling cluster to produce a balanced response. The signal integration mechanisms identified here may be widely used by other bacteria, since like R. sphaeroides, over 50\% of chemotactic bacteria have multiple {cheA} homologues and need to integrate signals from different sources. Chemotactic bacteria sense nutrient gradients and swim towards better environments for growth. A cluster of receptors in the cell membrane detects nutrient levels and signals via a cytoplasmic signaling pathway to the flagellum. The complexity of this signaling pathway varies across different bacterial species. The relatively simple pathway used by Escherichia coli is well understood; however, many bacteria, for example Rhodobacter sphaeroides, have more sophisticated pathways that, as well as being able to detect nutrients, are also able to assess the metabolic state of the cell. The receptors that detect metabolic state are located within an additional cluster that is physically distinct from the one that senses nutrients. In this work, we use a combination of experimentation and mathematical modeling to gain insight into the complex decision-making mechanisms that enable bacteria to weigh-up different stimuli and decide upon an appropriate response. We find novel communication mechanisms between the two signaling clusters that allow the outputs of the signaling pathways to be balanced and tuned according to the prevailing environmental conditions. The signaling principles identified here are likely to be used in other complex sensory networks.}, added-at = {2018-12-02T16:09:07.000+0100}, author = {Tindall, Marcus J. and Porter, Steven L. and Maini, Philip K. and Armitage, Judith P.}, biburl = {https://www.bibsonomy.org/bibtex/2a020e4c9b9625494f1c9b02af194a394/karthikraman}, citeulike-article-id = {7724825}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pcbi.1000896}, day = 19, doi = {10.1371/journal.pcbi.1000896}, interhash = {fb63baf6a45147db33a90880a9cfae87}, intrahash = {a020e4c9b9625494f1c9b02af194a394}, journal = {PLoS Comput Biol}, keywords = {chemotaxis}, month = aug, number = 8, pages = {e1000896+}, posted-at = {2010-09-01 09:36:38}, priority = {2}, publisher = {Public Library of Science}, timestamp = {2018-12-02T16:09:07.000+0100}, title = {Modeling Chemotaxis Reveals the Role of Reversed Phosphotransfer and a {Bi-Functional} {Kinase-Phosphatase}}, url = {http://dx.doi.org/10.1371/journal.pcbi.1000896}, volume = 6, year = 2010 }