Dataset Information

Crosstalk and the evolution of specificity in two-component signaling.

ABSTRACT: Two-component signaling (TCS) serves as the dominant signaling modality in bacteria. A typical pathway includes a sensor histidine kinase (HK) that phosphorylates a response regulator (RR), modulating its activity in response to an incoming signal. Most HKs are bifunctional, acting as both kinase and phosphatase for their substrates. Unlike eukaryotic signaling networks, there is very little crosstalk between bacterial TCS pathways; indeed, adding crosstalk to a pathway can have disastrous consequences for cell fitness. It is currently unclear exactly what feature of TCS necessitates this degree of pathway isolation. In this work we used mathematical models to show that, in the case of bifunctional HKs, adding a competing substrate to a TCS pathway will always reduce response of that pathway to incoming signals. We found that the pressure to maintain cognate signaling is sufficient to explain the experimentally observed "kinetic preference" of HKs for their cognate RRs. These findings imply a barrier to the evolution of new HK-RR pairs, because crosstalk is unavoidable immediately after the duplication of an existing pathway. We characterized a set of "near-neutral" evolutionary trajectories that minimize the impact of crosstalk on the function of the parental pathway. These trajectories predicted that crosstalk interactions should be removed before new input/output functionalities evolve. Analysis of HK sequences in bacterial genomes provided evidence that the selective pressures on the HK-RR interface are different from those experienced by the input domain immediately after duplication. This work thus provides a unifying explanation for the evolution of specificity in TCS networks.

SUBMITTER: Rowland MA

PROVIDER: S-EPMC3992699 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Crosstalk and the evolution of specificity in two-component signaling.

Rowland Michael A MA Deeds Eric J EJ

Proceedings of the National Academy of Sciences of the United States of America 20140331 15

Two-component signaling (TCS) serves as the dominant signaling modality in bacteria. A typical pathway includes a sensor histidine kinase (HK) that phosphorylates a response regulator (RR), modulating its activity in response to an incoming signal. Most HKs are bifunctional, acting as both kinase and phosphatase for their substrates. Unlike eukaryotic signaling networks, there is very little crosstalk between bacterial TCS pathways; indeed, adding crosstalk to a pathway can have disastrous conse ...[more]

PMID: 24706803

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Project description:UnlabelledTwo-component systems (TCS) comprise histidine kinases and their cognate response regulators and allow bacteria to sense and respond to a wide variety of signals. Histidine kinases (HKs) phosphorylate and dephosphorylate their cognate response regulators (RRs) in response to stimuli. In general, these reactions appear to be highly specific and require an appropriate association between the HK and RR proteins. The Myxococcus xanthus genome encodes one of the largest repertoires of signaling proteins in bacteria (685 open reading frames [ORFs]), including at least 127 HKs and at least 143 RRs. Of these, 27 are bona fide NtrC-family response regulators, 21 of which are encoded adjacent to their predicted cognate kinases. Using system-wide profiling methods, we determined that the HK-NtrC RR pairs display a kinetic preference during both phosphotransfer and phosphatase functions, thereby defining cognate signaling systems in M. xanthus. Isothermal titration calorimetry measurements indicated that cognate HK-RR pairs interact with dissociation constants (Kd) of approximately 1 µM, while noncognate pairs had no measurable binding. Lastly, a chimera generated between the histidine kinase, CrdS, and HK1190 revealed that residues conferring phosphotransfer and phosphatase specificity dictate binding affinity, thereby establishing discrete protein-protein interactions which prevent cross talk. The data indicate that binding affinity is a critical parameter governing system-wide signaling fidelity for bacterial signal transduction proteins.ImportanceUsing in vitro phosphotransfer and phosphatase profiling assays and isothermal titration calorimetry, we have taken a system-wide approach to demonstrate specificity for a family of two-component signaling proteins in Myxococcus xanthus. Our results demonstrate that previously identified specificity residues dictate binding affinity and that phosphatase specificity follows phosphotransfer specificity for cognate HK-RR pairs. The data indicate that preferential binding affinity is the basis for signaling fidelity in bacterial two-component systems.

Dataset Information

Crosstalk and the evolution of specificity in two-component signaling.

Publications

Crosstalk and the evolution of specificity in two-component signaling.

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