Structure and function of HWE/HisKA2-family sensor histidine kinases

•HWE and HisKA2 domain families comprise an unusual subset of sensor histidine kinases.•HWE/HisKA2 possess unique sequence motifs and structural features.•This kinase superfamily is involved in atypical two-component signaling processes.•HWE/HisKA2 are found in Alphaproteobacteria, select Gram-positives and archaea.

Sensor histidine kinases regulate adaptive cellular responses to changes in the chemical or physical state of the environment. HWE/HisKA2-family kinases comprise a subset of histidine kinases that is defined by unique sequence motifs in both the catalytic and non-catalytic regions. Recent crystal structures have defined conserved intramolecular interactions that inform models of kinase regulation that are unique to the HWE/HisKA2 superfamily. Emerging genetic, biochemical and genomic data indicate that, unlike typical histidine kinases, HWE/HisKA2 kinases do not generally signal via classical DNA-binding response regulators. Rather, these unusual kinases are often part of atypical regulatory pathways that control changes in gene expression via modulation of protein-protein interactions or transcription anti-termination.