Cross‐talk suppression between the CpxA–CpxR and EnvZ–OmpR two‐component systems in <i>E. coli</i>

Siryaporn, Albert; Goulian, Mark

doi:10.1111/j.1365-2958.2008.06426.x

Cited by 136 publications

(152 citation statements)

References 64 publications

(98 reference statements)

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“…Intensive experimental study over the past 10 years has revealed the biochemical and biophysical basis for this lack of promiscuity. In general, HKs demonstrate a strong "kinetic preference" for their cognate substrates, preferentially phosphorylating them on short timescales (7,15,16,(18)(19)(20)(21). A relatively small number of residues in the protein-protein interaction interface between HKs and RRs is responsible for maintaining this specificity (14)(15)(16)(20)(21)(22)(23).…”

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confidence: 99%

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Crosstalk and the evolution of specificity in two-component signaling

Rowland

Deeds

2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The global architectures of signaling networks in bacteria and eukaryotes are remarkably different: crosstalk between pathways is very common in eukaryotes but is very limited in bacteria. Bacteria use two-component signaling (TCS) to transduce information, relying on a single enzyme to act as both kinase and phosphatase for targets. We used mathematical models to show that introducing crosstalk in TCS always decreases system performance. This indicates that the large-scale differences between eukaryotic and bacterial networks likely derive from differences in the dynamics of the fundamental motifs from which the networks themselves are constructed. We further demonstrated that the pressure to avoid crosstalk has influenced the evolution of new TCS pairs, driving rapid sequence divergence in protein interaction interfaces immediately postduplication.

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confidence: 99%

“…Bacterial TCS networks show a remarkably different topology: HKs usually act on a single target (12)(13)(14)(15)(16)(17). Intensive experimental study over the past 10 years has revealed the biochemical and biophysical basis for this lack of promiscuity.…”

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confidence: 99%

Crosstalk and the evolution of specificity in two-component signaling

Rowland

Deeds

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Many response regulators can be nonspecifically phosphorylated by the cellular pool of acetylphosphate [18][19][20]; by acting as phosphatases for their cognate response regulators, histidine kinases effectively clear this spurious, signal-independent phosphorylation [21]. Consequently, mutations that eliminate the phosphatase activity of a histidine kinase, including deletion of the histidine kinase gene, can lead to the inappropriate activation of the kinase's cognate response regulator under non-inducing conditions (Fig.…”

Section: Mechanisms Ensuring Specificity In Two-component Signaling Pmentioning

confidence: 99%

“…Consequently, mutations that eliminate the phosphatase activity of a histidine kinase, including deletion of the histidine kinase gene, can lead to the inappropriate activation of the kinase's cognate response regulator under non-inducing conditions (Fig. 2a) [21].…”

Section: Mechanisms Ensuring Specificity In Two-component Signaling Pmentioning

confidence: 99%

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Determinants of specificity in two-component signal transduction

Podgornaia

Laub

2013

Current Opinion in Microbiology

129

133

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Maintaining the faithful flow of information through signal transduction pathways is critical to the survival and proliferation of organisms. This problem is particularly challenging as many signaling proteins are part of large, paralogous families that are highly similar at the sequence and structural levels, increasing the risk of unwanted cross-talk. To detect environmental signals and process information, bacteria rely heavily on two-component signaling systems comprised of sensor histidine kinases and their cognate response regulators. Although most species encode dozens of these signaling pathways, there is relatively little cross-talk, indicating that individual pathways are well insulated and highly specific. Here, we review the molecular mechanisms that enforce this specificity. Further, we highlight recent studies that have revealed how these mechanisms evolve to accommodate the introduction of new pathways by gene duplication.3

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Regulatory Systems: Two‐Component

Raivio

2019

Encyclopedia of Life Sciences

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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 d imer of two alpha helices connected by a flexible linker that makes a four‐helical bundle and contains the conserved h istidine that is the site of auto p hosphorylation. 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.

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Cross‐talk suppression between the CpxA–CpxR and EnvZ–OmpR two‐component systems in E. coli

Cited by 136 publications

References 64 publications

Crosstalk and the evolution of specificity in two-component signaling

Crosstalk and the evolution of specificity in two-component signaling

Determinants of specificity in two-component signal transduction

Regulatory Systems: Two‐Component

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