Regulatory Systems: Two‐Component

Abstract

Two‐component signal transduction (TCST) systems constitute a large class of regulatory proteins that function as signal transducers. Each system comprises a sensor or histidine kinase (HK) and an effector or response regulator (RR), which communicate through a conserved set of phosphotransfer reactions to effect adaptive changes in response to specific environmental signals. HKs and RRs are modular in nature, with variable sensory and output structures appended to the conserved domains that facilitate phosphotransfer mediated signal transduction. Input signals trigger successive conformational changes in domains and protein:protein interactions that alter phosphotransfer, and ultimately an output response mediated by the phosphorylated RR. TCST systems are abundant in bacteria and many microbes utilise multiple TCST pathways to sense and respond to a plethora of environmental and physiological changes. Specificity between cognate HKs and RRs is largely maintained through co‐evolving residues at a conserved interface where the RR docks on the HK. TCST systems are integrated into cellular signalling networks and interact with macromolecules and proteins that connect them to salient regulatory pathways and cellular functions. The current state of knowledge around TCST systems will be summarised, emphasising findings published since the first version of this article in 2006.

Key Concepts

  • A prototypical two‐component system is made up of a membrane‐bound sensory histidine kinase that senses a unique environmental or cellular parameter and a cytoplasmic response regulator that controls an adaptive response.
  • HKs and RRs communicate through phosphotransfer reactions that are mediated by conserved domains; signal sensing alters the ratio of HK kinase to phosphatase activity to change the function of the RR by altering its phosphorylation status.
  • HKs and RRs are organised in a modular fashion; a variety of sensing domains can be appended to the HK enzymatic module while diverse output domains with DNA binding, RNA binding, enzymatic activity or protein binding functions are often fused to the C‐terminal end of the response regulator phosphorylated receiver (REC) domain.
  • The HK is a dimer containing a catalytic domain composed of two DHp and CA domains. The DHp domain consists of a dimer of two alpha helices connected by a flexible linker that makes a four‐helical bundle and contains the conserved histidine that is the site of autophosphorylation. The CA domain resembles other ATP‐binding folds and is the enzymatic portion of the HK.
  • The RR consists at its N‐terminus of the conserved receiver (REC) domain, which consists of a five‐stranded beta sheet surrounded by alpha helices and contains the conserved aspartate that is the site of phosphorylation.
  • Signals are detected through conformational changes in a sensory domain that are propagated through some combination of rotational, piston and order to disorder transitions by alpha‐helical transduction elements to the cytoplasmic enzymatic domain of the HK. These movements lead to alterations in HK dimer symmetry that dictate kinase or phosphatase activity.
  • In the inactive state, the cytoplasmic DHp and CA domains of the HK are organised in a symmetrical fashion with the CA domain juxtaposed against the membrane‐proximal end of the DHp four‐helical bundle. The RR REC domain can interact with the inactive HK DHp four‐helical bundle at a more membrane‐distal location in an orientation that would facilitate dephosphorylation of the aspartate.
  • The active, kinase state of the HK is asymmetrical due to a bend or kink in the DHp domain that leads to one CA domain adopting a looser association that positions it well for phosphorylation of a histidine residue. A single RR REC domain can bind near the other CA domain, which is more closely associated with the DHp domain, in a conformation supporting phosphorylation of the aspartate residue utilising the phosphorylated histidine as a substrate.
  • Repeated cycles of DHp domain bending and RR REC domain binding are hypothesised to support successive rounds of HK autophosphorylation and RR phosphorylation in response to signal inputs received from the sensory domain.
  • HKs and RRs regulate and interact with other macromolecules and proteins to connect signalling pathways, coordinate their activities and sense environmental parameters and changes to cellular physiology.

Keywords: two‐component; histidine kinase; response regulator; signal transduction

Figure 1. Paradigms for a two‐component signal transduction pathway (a) and a phosphorelay (b). The histidine kinase (HK) functions as a dimer and most consist of a sensor (S) domain localised to the periplasm or exterior of the cell by two transmembrane domains (navy blue rectangles), an alpha‐helical signalling domain (grey rectangle), a DHp (dimerisation histidine phosphotransfer) domain (light green rectangles) containing the conserved Histidine residue (small white pentagon), and catalytic and ATP‐binding (CA) domain (dark green circle). The RR (red and orange) is made up of an N‐terminal REC (receiver) domain and a C‐terminal output (O) domain. Signal‐induced conformational changes result in phosphorylation of one Histidine per dimer by the CA domain, through ATP hydrolysis. The REC domain is subsequently phosphorylated at a conserved Aspartate residue (zig–zag black line) using the phosphorylated His residue in the HK as a substrate. Phosphorylation of the REC domain leads to an output, mediated by the attached output domain. In the phosphorelay (b) phosphate travels from a His in the HK DHp domain to a REC domain and then a histidine phosphotransfer domain (HPt, light blue rectangle) before finally phosphorylating the REC domain Aspartate. The extra phosphorylation steps permit for additional regulatory inputs.
Figure 2. Two‐component signal transduction systems are made up of a variety of sensing domains and output domains that are joined in a modular fashion to the DHp (dimerisation histidine phosphotransfer, light green rectangles) and CA domains (catalytic ATP binding, dark green circle) of the HK (histidine kinase) or the REC (receiver) domain (red rectangle) of the RR, respectively. Signal sensing can be accomplished through PDC (PhoQ, DcuS, CitA) or all alpha‐helical domains located outside the cytoplasm and connected to the DHp and CA domains by transmembrane domains (dark blue rectangles) and/or alpha helical signalling elements (HAMP domains, grey rectangles; S helices, grey squiggly line). Signal sensing is also mediated in some cases by the TM (transmembrane) domains themselves, or by cytoplasmic PDC/GAF (cGMP‐specific phosphodiesterases, adenylyl cyclases, FhlA) domains (light green oval). Upon phosphorylation of the REC domain, the response is mediated by one of many possible adjoined output domains, including DNA‐binding (orange), RNA‐binding (pink rectangle) and enzymatic (light orange hexagon) effector modules.
Figure 3. HKs (histidine kinases) adopt distinct conformations in the inactive (phosphatase) and active (kinase) states. An inactive HK may function as a phosphatase (left). In this conformation, the dimer adopts a symmetrical conformation in which the CA (catalytic ATP binding) domains interact with the DHp (dimerisation histidine phosphotransfer) domains (light green rectangles) at the membrane‐proximal end, while the REC (receiver) domain of the RR (response regulator) binds further down the DHp four‐helical bundle such that the HK His and RR Asp domains are positioned appropriately for hydrolysis. In the active kinase state (right), the DHp domains adopt an asymmetric bent orientation in which one CA domain interacts loosely with the DHp domain and is positioned appropriately for phosphorylation of one of the DHp histidines. The other CA domain interacts more extensively with the DHp helical bundle, and the REC domain of a single RR is positioned appropriately for phosphotransfer between the conserved histidine and aspartate amino acids. The HK is thought to undergo significant conformational changes involving bending of the DHp domain stimulated by signal sensing during repeated cycles of potentially simultaneous autophosphorylation and phosphotransfer to the REC domain.
Figure 4. Phosphorylation of the RR REC (receiver) domain alters the α4‐β5‐α5 face (green rectangle) to remove inhibitory (top left), or stimulate activating (right side) protein–protein interactions between REC domains (top and bottom right) or between the REC domain and other proteins (blue hexagon) or output domains (turquoise triangle).
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Further Reading

Bhate MP, Molnar KS, Goulian M and DeGrado WF (2015) Signal transduction in histidine kinases: insights from new structures. Structure 23: 981–994.

Bourret RB (2010) Receiver domain structure and function in response regulator proteins. Current Opinion in Microbiology 13: 142–149.

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Gao R and Stock AM (2010) Molecular strategies for phosphorylation‐mediated regulation of response regulator activity. Current Opinion in Microbiology 13: 160–167.

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Silversmith RE (2010) Auxiliary phosphatases in two‐component signal transduction. Current Opinion in Microbiology 13: 177–183.

Wuichet K, Cantwell BJ and Zhulin IB (2010) Evolution and phyletic distribution of two‐component signal transduction systems. Current Opinion in Microbiology 13: 219–225.

Zschiedrich CP, Keidel V and Szurmant H (2016) Molecular mechanisms of two‐component signal transduction. Journal of Molecular Biology 428: 3752–3775.

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Raivio, Tracy L(May 2019) Regulatory Systems: Two‐Component. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000856.pub3]