Chapter 2 : Two-Component Signal Transduction and Chemotaxis

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This chapter provides a review of the architecture and structures of histidine kinases (HKs) and response regulators (RRs) and a description of a well-characterized two component system, the bacterial chemotaxis signaling pathway. In addition, the potential of two-component systems as drug targets and the progress that has been made with inhibitor design and development are discussed. Two-component signal transduction systems are structured around two conserved proteins: an HK and an RR. An important area of research focuses on understanding how phosphorylation of the conserved regulatory domain affects the activities of the structurally and functionally diverse effector domains. Chemotaxis proteins were among the first HK and RRs for which biochemical activities were defined and for which three-dimensional structures were determined. In the enteric bacterium , the chemotaxis signaling pathway controls the direction of flagellar rotation; counterclockwise flagellar rotation produces smooth-swimming behavior, and clockwise rotation produces tumbling, allowing reorientation. CheB, which demethylates the chemotaxis receptors, is the primary locus of regulation. The emergence of multiple drug resistance is an increasing problem. The chapter discusses several classes of two-component systems that are attractive drug targets. Two-component regulatory systems are involved in many aspects of motility, including the regulation of expression of genes encoding the motility apparatus and chemotaxis. The well-conserved CheA-CheY-CheB components that mediate chemotaxis are discussed. The chapter describes the results of chemical library screening and initial attempts at rational design of inhibitors.

Citation: Lubetsky J, Stock A. 2005. Two-Component Signal Transduction and Chemotaxis, p 17-36. In Waksman G, Caparon M, Hultgren S (ed), Structural Biology of Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555818395.ch2
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Figure 1.

Schematic diagram of bacterial chemotaxis signal transduction. External stimuli trigger changes in protein modifications and protein-protein interactions that lead to behavioral responses generated by the flagellar motors, as described in the text. The proteins present in the chemotaxis system are shown as circles. CheC, CheD, and CheV (squares) are absent in but are present in a large number of other bacteria.

Citation: Lubetsky J, Stock A. 2005. Two-Component Signal Transduction and Chemotaxis, p 17-36. In Waksman G, Caparon M, Hultgren S (ed), Structural Biology of Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555818395.ch2
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