Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions [1]. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk [2]. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more [3]. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) [4]. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [5, 6].

Bipartite response regulator proteins are involved in a two-component signal transduction system in bacteria, and certain eukaryotes like protozoa, that functions to detect and respond to environmental changes [7]. These systems have been detected during host invasion, drug resistance, motility, phosphate uptake, osmoregulation, and nitrogen fixation, amongst others [8]. The two-component system consists of a histidine protein kinase environmental sensor that phosphorylates the receiver domain of a response regulator protein; phosphorylation induces a conformational change in the response regulator, which activates the effector domain, triggering the cellular response [9]. The domains of the two-component proteins are highly modular, but the core structures and activities are maintained.

The response regulators act as phosphorylation-activated switches to affect a cellular response, usually by transcriptional regulation. Most of these proteins consist of two domains, an N-terminal response regulator receiver domain, and a variable C-terminal effector domain with DNA-binding activity. This entry represents the response regulator receiver domain, which belongs to the CheY family, and receives the signal from the sensor partner in the two-component system.

1. Two-component signal transduction pathways regulating growth and cell cycle progression in a bacterium: a system-level analysis. PLoS Biol. 3, e334
2. Specificity in two-component signal transduction pathways. Annu. Rev. Genet. 41, 121-45
3. Histidine protein kinases: key signal transducers outside the animal kingdom. Genome Biol. 3, REVIEWS3013
4. Two-component signal transduction. Annu. Rev. Biochem. 69, 183-215
5. Molecular recognition of bacterial phosphorelay proteins. Curr. Opin. Microbiol. 5, 142-8
6. Keeping signals straight in phosphorelay signal transduction. J. Bacteriol. 183, 4941-9
7. Response regulators of bacterial signal transduction systems: selective domain shuffling during evolution. J. Mol. Evol. 40, 136-54
8. Tandem DNA recognition by PhoB, a two-component signal transduction transcriptional activator. Structure 10, 701-13

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide
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