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Review
. 2012:66:325-47.
doi: 10.1146/annurev-micro-092611-150039. Epub 2012 Jun 28.

Evolution of two-component signal transduction systems

Emily J Capra  1 , Michael T Laub
Affiliations
Review

Evolution of two-component signal transduction systems

Emily J Capra et al. Annu Rev Microbiol. 2012.

Abstract

To exist in a wide range of environmental niches, bacteria must sense and respond to a variety of external signals. A primary means by which this occurs is through two-component signal transduction pathways, typically composed of a sensor histidine kinase that receives the input stimuli and then phosphorylates a response regulator that effects an appropriate change in cellular physiology. Histidine kinases and response regulators have an intrinsic modularity that separates signal input, phosphotransfer, and output response; this modularity has allowed bacteria to dramatically expand and diversify their signaling capabilities. Recent work has begun to reveal the molecular basis by which two-component proteins evolve. How and why do orthologous signaling proteins diverge? How do cells gain new pathways and recognize new signals? What changes are needed to insulate a new pathway from existing pathways? What constraints are there on gene duplication and lateral gene transfer? Here, we review progress made in answering these questions, highlighting how the integration of genome sequence data with experimental studies is providing major new insights.

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Figures

Figure 1
Figure 1. Overview of two-component signal transduction
(a) In the prototypical two-component pathway (left), the catalytic and ATPase (CA) domain of a histidine kinase binds ATP and autophosphorylates a conserved histidine in the dimerization and histidine phosphotransferase (DHp) domain. The phosphoryl group is then transferred to an aspartate in the receiver domain (RD) of the cognate response regulator, activating its output domain to effect cellular changes, frequently through changes in transcription. In a phosphorelay (right), a hybrid histidine kinase autophosphorylates and transfers its phosphoryl group intramolecularly to a receiver domain. A histidine phosphotransferase (HPT) then shuttles the phosphoryl group to a soluble response regulator that effects a pathway output. (b) Common domain organizations of histidine kinases and response regulators. For histidine kinases, the DHp and CA domains are shown with common intracellular domains, PAS, HAMP, and GAF. Note that some kinases have multiple copies of such domains. Two transmembrane domains (TM) are shown on the kinases, but kinases can harbor from 1-13 TM domains. A wide range of sensory domains (not shown) are often found in the periplasmic portions of membrane-bound histidine kinases. For response regulators, the conserved receiver domain is shown alone or with the common output domains, a DNA-binding domain (DBD), a AAA+ and DBD, a GGDEF domain involved in cyclic-di-GMP synthesis, or a CheB-like methyltransferase domain.
Figure 2
Figure 2. Diversity of two-component signaling gene content in bacterial genomes
(a) Plot showing the number of histidine kinases and response regulators in a range of organisms. Generally, most genomes contain equal numbers of kinases and regulators, as pathways typically comprise a kinase and one cognate regulator. When the ratio is not 1:1, there are usually more kinases than regulators, suggesting that response regulators may sometimes integrate signals from multiple kinases. (b) Plot showing the number of two-component proteins as a function of genome size for the same organisms as in panel (a). Each plot is based on 504 bacterial genomes (22). A handful of well-studied and notable species are marked with red squares.
Figure 3
Figure 3. Evolution of transcriptional circuits controlled by two-component pathways
(a) Examples of genes directly regulated by the two-component pathway PhoQ-PhoP in S. enterica and Y. pestis. The gene slyB is conserved, and directly regulated by PhoP, in both species. The genes rstA and psiE are conserved, but directly regulated by PhoP in only one of the two species. The directly regulated genes ugtL and y4126 are unique to S. enterica and Y. pestis, respectively. (b) Schematic of S. bongori and S. enterica chromosomes, each harboring a srfN ortholog. The horizontally-acquired SpiR-SsrB system, encoded on Salmonella pathogenicity island-2 (SPI-2) in S. enterica but not S. bongori, evolved to transcriptionally activate srfN. (b) De novo evolution of a response regulator binding site. SPI-2 encodes the two-component pathway SpiR-SsrB, which was acquired after the divergence of S. enterica from S. bongori. The gene srfN, ancestral to the Salmonella lineage, accumulated promoter mutations that enabled activation by SsrB, a transcriptional link that contributes to Salmonella virulence. The relevant portion of the srfN promoter is shown with conserved positions shaded grey and the region bound by SsrB in S. enterica underlined.
Figure 4
Figure 4. Amino-acid coevolution in two-component signaling proteins
(a) Residues that coevolve in cognate pairs of histidine kinases and response regulators are shown with spacefilling on the crystal structure of the T. maritima kinase TM0853, shown in blue, bound to its cognate regulator TM0468, shown in green. The histidine and the aspartate that are involved in phosphotransfer are shown in purple. Coevolving residues on the histidine kinase and response regulator are shown with spacefilling and colored orange and red, respectively. Residues in histidine kinases that coevolve strongly with other kinase residues are shown with spacefilling and colored cyan. (b–c) Coevolving residues from panel (a) are shown on a sequence alignment of TM0853 with three E. coli kinases, EnvZ, RstB, and CpxA (b), and an alignment of TM0468 with three E. coli regulators, OmpR, RstA, and CpxR (c). Highly conserved residues are shaded grey. Secondary structure elements are indicated beneath the primary sequence.
Figure 5
Figure 5. Insulation of two-component pathways following gene duplication
(a) Schematic of major steps in the insulation of two pathways following a duplication event. The duplication of an ancestral pathway initially produces two identical pathways that cross-talk at the level of phosphotransfer. Through the accumulation of mutations in specificity-determining residues, the two pathways can become insulated. A similar process must occur, but is not shown, at the levels of kinase and regulator homodimerization. (b) Phosphotransfer specificity of EnvZ, RstB, and various RstB mutants. Each kinase was autophosphorylated and tested for transfer to each of three response regulators, RstA, OmpR, and CpxR. Data are from (10). The wild-type RstB is shown at far left. The phosphotransfer specificity can be converted to that of EnvZ, shown at far right, by mutating three of its six specificity- determining residues to match those found in EnvZ (the other three sites are already identical between EnvZ and RstB; see Fig. 4b). This triple mutant of RstB as well as each single and double mutant intermediate are labeled based on the identity of the three specificity residues with blue text indicating identity with the wild-type RstB and red indicating identity with the wild-type EnvZ. Notably, some intermediates do not phosphorylate any of the regulators whereas some phosphorylate all three. (c) Schematic summarizing the distribution of histidine kinases in the sequence space defined by their specificity-determining residues. Each sphere represents the set of response regulators that a given kinase phosphorylates. With the exception of NarQ and NarX, these spheres are presented as non-overlapping to reflect the minimal cross-talk between pathways. The relative positions of spheres is based on the ability of individual kinases to phosphorylate the cognate response regulators of other kinases after extended times in vitro (74; 92). Positions are approximate and the diagram is only intended to convey a general sense of how kinases are distributed in sequence space. Spheres are colored according to the subfamily of each kinase’s response regulator: red, CheY/receiver domain only; pink, OmpR/winged helix-turn-helix; green, NtrC/AAA+ and FIS domains; blue, NarL/GerE helix-turn-helix; brown, LytR. Spheres with dashed outlines indicate kinases for which no data existed to infer relative positions. Note, hybrid histidine kinases are excluded.
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