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

Nat Commun. 2020 Feb 7;11(1):769. doi: 10.1038/s41467-020-14540-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Outer Membrane Proteins / chemistry
  • Bacterial Outer Membrane Proteins / metabolism
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism
  • Catalysis
  • Crystallography, X-Ray
  • Escherichia coli Proteins / chemistry
  • Escherichia coli Proteins / metabolism
  • Histidine / metabolism
  • Histidine Kinase / chemistry*
  • Histidine Kinase / genetics
  • Histidine Kinase / metabolism*
  • Hydrogen-Ion Concentration
  • Models, Biological
  • Models, Molecular
  • Multienzyme Complexes / chemistry
  • Multienzyme Complexes / metabolism
  • Mutation
  • Phosphorylation
  • Protein Conformation
  • Thermotoga maritima / enzymology*
  • Thermotoga maritima / genetics
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism


  • Bacterial Outer Membrane Proteins
  • Bacterial Proteins
  • Escherichia coli Proteins
  • Multienzyme Complexes
  • Trans-Activators
  • osmolarity response regulator proteins
  • Histidine
  • Histidine Kinase
  • envZ protein, E coli