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.
Highlights
Two-component signaling pathways are the major mechanism by which bacterial cells sense and respond to changes in their environment
Construction of the mathematical model Within an R. sphaeroides cell, CheA2 has been shown to localize to the polar chemotaxis cluster, while CheA3 and CheA4 localize to the cytoplasmic cluster [44]
What is the reason for this discrimination and how does it contribute towards the chemotactic response of the cell? To understand the role of each signaling cluster we constructed an ordinary differential equation (ODE) model of an R. sphaeroides cell as detailed in Text S1
Summary
Two-component signaling pathways are the major mechanism by which bacterial cells sense and respond to changes in their environment. They regulate processes as diverse as virulence, gene expression, development and motility [1]. Bacteria can have over 100 different two-component pathways per cell, one form of which controls swimming behavior. Most chemotactic bacteria sense changes in their extracellular environment using transmembrane chemoreceptors [11]. These chemoreceptors signal via an intracellular signaling cascade to the flagellar motor. The chemoreceptors detect changes in the periplasmic chemoeffector concentration and control the rate at which CheA autophosphorylates on a conserved histidine residue. CheY-P and CheB-P both naturally autodephosphorylate [27], the rate of CheY-P dephosphorylation is enhanced by CheZ to allow signal termination within the time required for effective gradient sensing [28,29]
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