Bacterial Two-Component Systems: Structures and Signaling Mechanisms

Two-component systems (TCS) are ubiquitous among bacteria. They play essential roles in signaling events in bacteria, such as cell-cell communication, adaptation to environments, and pathogenesis in the case of pathogens. Due to their absence in humans and other mammals, TCS proteins are considered potential targets for developing new antibiotics. Most bacterial TCSs consist of two proteins, a sensor histidine kinase (HK) and a response regulator (RR). The HK senses specific signals, and that leads to activation of the kinase activity and autophosphorylation of a conserved histidine residue. The phosphoryl group is subsequently transferred to a cognate response regulator to activate its activities. Most RRs are transcription regulators and turn on or off gene transcriptions in response to the signals received by sensor HKs. Recent years have seen a rapid expansion of structural data of bacterial TCS proteins. In this chapter, I will review structures of HKs and RRs and discuss their structure-function relationship and their signaling mechanisms. The chapter contains three main sections: structures of histidine kinases, structures of response regulators, and structures of complexes between a histidine kinase and a response regulator. I will conclude the chapter with the implications of these structural and functional data on developments of new therapeutics against bacterial pathogens. Analysis of structures and reaction mechanisms will focus on the extracytosolic sensor HKs and OmpR/PhoB subfamily transcription regulator RRs.