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Chapter 4 : The Role of Two-Component Signal Transduction Systems in Bacterial Stress Responses
Category: Microbial Genetics and Molecular Biology
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This chapter discusses the state of our understanding of two-component pathways on all levels, beginning with the initial input stimulus through the final output response. Its goal is to demonstrate the key principles and paradigms for how these signaling pathways work by drawing on specific, illustrative examples. Two-component signaling proteins are among the most prevalent signaling molecules in the bacterial kingdom and represent a primary means by which bacteria sense and respond to a range of stresses and environments. In many cases, histidine kinases are bifunctional: acting as both kinases and phosphatases for their cognate substrates. All histidine kinases have two conserved domains: the dimerization and phosphotransfer (DHp) domain and the catalytic and ATP-binding (CA) domain. Most bacteria are faced with a constantly changing environment and a multitude of stressors that challenge their survival. Two-component signaling proteins are one of the predominant means by which bacteria sense and respond to such challenges. Since their initial discovery two decades ago, histidine kinases and response regulators have been implicated in countless stress responses. But it remains a major challenge to understand how cells evolve new signaling pathways to respond to new stressors.
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(A) Schematic of the canonical two-component signaling system. In response to an input signal, the sensor histidine kinase uses ATP to autophosphorylate. The phosphoryl group is then transferred to a cognate response regulator to trigger an output. The symbol ~P indicates phosphorylation of the conserved histidine and aspartate in the histidine kinase and response regulator, respectively. (B) Schematic of a phosphorelay. After autophosphorylation, the hybrid histidine kinase will transfer the phosphoryl group intramolecularly to a response regulator-like domain. A histidine phosphotransferase then shuttles the phosphoryl group to a soluble response regulator that affects an output. In some cases, the hybrid kinase is split into a canonical histidine kinase and soluble response regulator (see, for example, Fig. 2A ).
Schematics of the phosphorelays controlling (A) sporulation in B. subtilis, (B) quorum-sensing in V. harveyi, and (C) the cell cycle in C. crescentus. The two-component signaling proteins in each panel are shaded in gray. Also shown are the auxiliary proteins that regulate phosphate flow through the pathway (see text for details), as well as the inputs and outputs for each pathway.
(A) Domain architecture of response regulators. Six of the most common domains found adjacent to the receiver domain that is phosphorylated are shown (Galperin, 2006 ). Three are involved in DNA-binding and the regulation of transcription: wHTH (winged helix-turn-helix), HTH (helix-turn-helix), and AAA+ ATPase/FIS. Two are associated with cyclic-di-GMP signaling— GGDEF and EAL domains—each named for a conserved patch of residues that synthesize and degrade c-di-GMP, respectively. Many response regulators are also single-domain proteins and harbor only a phosphorylatable receiver domain. (B) Domain architecture of histidine kinases. The four most common domains found adjacent to the DHp and CA domains are PAS, HAMP, GAF, and TM (transmembrane) domains (Galperin, 2006 ). In many cases, the linker between the input and DHp domains is a so-called signaling, or S, helix. Note that the diagram only indicates the most proximal domain, but many histidine kinases contain multiple domains N-terminal to the DHp domain.