Evolutionary history expands the range of signaling interactions in hybrid multikinase networks

Philippe Ortet, Sylvain Fochesato, Anne-Florence Bitbol, David E. Whitworth, David Lalaouna, Catherine Santaella, Thierry Heulin, Wafa Achouak, Mohamed Barakat*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Two-component systems (TCSs) are ubiquitous signaling pathways, typically comprising a sensory histidine kinase (HK) and a response regulator, which communicate via intermolecular kinase-to-receiver domain phosphotransfer. Hybrid HKs constitute non-canonical TCS signaling pathways, with transmitter and receiver domains within a single protein communicating via intramolecular phosphotransfer. Here, we report how evolutionary relationships between hybrid HKs can be used as predictors of potential intermolecular and intramolecular interactions (‘phylogenetic promiscuity’). We used domain-swap genes chimeras to investigate the specificity of phosphotransfer within hybrid HKs of the GacS–GacA multikinase network of Pseudomonas brassicacearum. The receiver domain of GacS was replaced with those from nine donor hybrid HKs. Three chimeras with receivers from other hybrid HKs demonstrated correct functioning through complementation of a gacS mutant, which was dependent on strains having a functional gacA. Formation of functional chimeras was predictable on the basis of evolutionary heritage, and raises the possibility that HKs sharing a common ancestor with GacS might remain components of the contemporary GacS network. The results also demonstrate that understanding the evolutionary heritage of signaling domains in sophisticated networks allows their rational rewiring by simple domain transplantation, with implications for the creation of designer networks and inference of functional interactions.

Original languageEnglish
Article number11763
Pages (from-to)11763
Number of pages12
JournalScientific Reports
Issue number1
Early online date03 Jun 2021
Publication statusPublished - 01 Dec 2021


  • Bacterial Proteins/genetics
  • Biological Evolution
  • Phenotype
  • Phosphorylation
  • Phylogeny
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Kinases/genetics
  • Pseudomonas/classification
  • Signal Transduction


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