Central role of the BvgS receiver as a phosphorylated intermediate in a complex two-component phosphorelay

Two-component systems use phosphorylation reactions to regulate stimulus/response pathways. In Bordetella pertussis, a human respiratory pathogen, the infectious cycle of the organism is controlled by the BvgAS two-component system. BvgS has similarities to sensor and response regulator components and is an autophosphorylating kinase that phosphorylates BvgA. BvgA, a response regulator, is a DNA-binding protein that activates virulence gene transcription. Three phosphorylated BvgS domains, the transmitter, receiver, and C terminus, are essential for signal transduction. We now demonstrate that the BvgS transmitter is sufficient for autophosphorylation but is unable to phosphorylate the C terminus or BvgA. The BvgS receiver regulates several phenotypes: dephosphorylation of both the BvgS transmitter and C terminus as well as transfer of a phosphoryl group from the transmitter to the C terminus. Our results indicate that BvgAS signal transduction initiates with autophosphorylation of the transmitter followed by phosphotransfer to the receiver. The phosphorylated receiver can donate to the C terminus or to water. The phosphorylated C terminus is then able to transfer the phosphoryl group to BvgA.