Revisiting the pH-gated conformational switch on the activities of HisKA-family histidine kinases

Histidine is a versatile residue playing key roles in enzyme catalysis thanks to the chemistry of its imidazole group that can serve as nucleophile, general acid or base depending on its protonation state. In bacteria, signal transduction relies on two-component systems (TCS) which comprise a sensor histidine kinase (HK) containing a phosphorylatable catalytic His with phosphotransfer and phosphatase activities over an effector response regulator. Recently, a pH-gated model has been postulated to regulate the phosphatase activity of HisKA HKs based on the pH-dependent rotamer switch of the phosphorylatable His. Here, we have revisited this model from a structural and functional perspective on HK853-RR468 and EnvZ-OmpR TCS, the prototypical HisKA HKs. We have found that the rotamer of His is not influenced by the environmental pH, ruling out a pH-gated model and confirming that the chemistry of the His is responsible for the decrease in the phosphatase activity at acidic pH

We're in this Together: Sensation of the Host Cell Environment by Endosymbiotic Bacteria

Bacteria inhabit diverse environments, including the inside of eukaryotic cells. While a bacterial invader may initially act as a parasite or pathogen, a subsequent mutualistic relationship can emerge in which the endosymbiotic bacteria and their host share metabolites. While the environment of the host cell provides improved stability when compared to an extracellular environment, the endosymbiont population must still cope with changing conditions, including variable nutrient concentrations, the host cell cycle, host developmental programs, and host genetic variation. Furthermore, the eukaryotic host can deploy mechanisms actively preventing a bacterial return to a pathogenic state. Many endosymbionts are likely to use two-component systems (TCSs) to sense their surroundings, and expanded genomic studies of endosymbionts should reveal how TCSs may promote bacterial integration with a host cell. We suggest that studying TCS maintenance or loss may be informative about the evolutionary pathway taken toward endosymbiosis, or even toward endosymbiont-to-organelle conversion.Peer reviewe

Protein Dynamics in Phosphoryl-Transfer Signaling Mediated by Two-Component Systems

International audienceThe ability to perceive the environment, an essential attribute in living organisms, is linked to the evolution of signaling proteins that recognize specific signals and execute predetermined responses. Such proteins constitute concerted systems that can be as simple as a unique protein, able to recognize a ligand and exert a phenotypic change, or extremely complex pathways engaging dozens of different proteins which act in coordination with feedback loops and signal modulation. To understand how cells sense their surroundings and mount specific adaptive responses, we need to decipher the molecular workings of signal recognition, internalization, transfer, and conversion into chemical changes inside the cell. Protein allostery and dynamics play a central role. Here, we review recent progress on the study of two-component systems, important signaling machineries of prokaryotes and lower eukaryotes. Such systems implicate a sensory histidine kinase and a separate response regulator protein. Both components exploit protein flexibility to effect specific conformational rearrangements, modulating protein-protein interactions, and ultimately transmitting information accurately. Recent work has revealed how histidine kinases switch between discrete functional states according to the presence or absence of the signal, shifting key amino acid positions that define their catalytic activity. In concert with the cognate response regulator's allosteric changes, the phosphoryl-transfer flow during the signaling process is exquisitely fine-tuned for proper specificity, efficiency and directionality