Systems Biology Approach to Study the Escherichia coli Two-Component Signal Transduction Interactome

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All organisms make continual adjustments to account for changes in their environments. Single celled microbes use a family of proteins called two-component regulators to sense alterations in their environments and institute adaptive changes. Each two-component system consists of a sensor protein that is exposed to the outside of the cell to detect environmental parameters and a regulator protein that communicates with the sensor and makes appropriate changes in gene expression. A microbe may possess tens or hundreds of two-component systems, each one responsive to a different environmental cue. Recent studies indicate that some two-component systems are connected by means of signaling proteins called connectors. Connectors are turned on by one two-component system and influence the signaling activities of another two-component system. These connections allow for the formation of a cellular regulatory network that results in optimal adaptation to a given signal by integrating the activities of multiple two-component systems. In this proposal, I hypothesize that additional, undiscovered connections exist between the 30 two-component systems of the well-characterized model organism Escherichia coli. We will first identify connected two-component systems by comparing gene expression profiles obtained when individual two-component pathways are turned on. Once we have identified connections between two-component systems, we will use genetic screens to identify the "connectors" that are responsible for making the connections. Finally, we will figure out how these connectors work. Previously identified connectors work by interacting with the sensor or the regulator of the affected two-component system to alter its activity. We will set up experiments to evaluate which member of the two-component system is affected by the connector, and how. Since two-component regulators play important roles in controlling bacterial activities involved in disease causation and metabolism, this work has the potential to uncover new ideas about how to treat microbial infections and how to harness bacteria for the production of useful compounds.