Structural Insight into the Role of the PAS Domain for Signal Transduction in Sensor Kinase BvgS

The two-component system BvgAS controls the virulence regulon in Bordetella pertussis. BvgS is the prototype of a family of sensor histidine kinases harboring periplasmic Venus flytrap (VFT) domains. The VFT domains are connected to the cytoplasmic kinase moiety by helical linkers separated by a Per-ARNT-Sim (PAS) domain. Antagonism between the two linkers, as one forms a coiled coil when the other is dynamic and vice versa, regulates BvgS activity. Here, we solved the structure of the intervening PAS domain by X-ray crystallography. Two forms were obtained that notably differ by the connections between the PAS core domain and the flanking helical linkers. Structure-guided mutagenesis indicated that those connections participate in the regulation of BvgS activity. Thus, the PAS domain appears to function as a switch facilitator module whose conformation determines the output of the system. As many BvgS homologs have similar architectures, the mechanisms unveiled here are likely to generally apply to the regulation of sensor histidine kinases of that family. IMPORTANCE The whooping cough agent Bordetella pertussis colonizes the human respiratory tract by using virulence factors coregulated by the sensory transduction system BvgAS. BvgS is a model for a family of sensor kinase proteins, some of which are found in important bacterial pathogens. BvgS functions as a kinase or a phosphatase depending on external signals, which determines if B. pertussis is virulent or avirulent. Thus, deciphering its mode of action might lead to new ways of fighting infections. Here, we used X-ray crystallography to solve the three-dimensional structure of the domain that precedes the enzymatic moiety and identified features that regulate BvgS activity. As many sensor kinases of the BvgS family harbor homologous domains, the mechanism unveiled here might be of general relevance.

Automated summary

The BvgAS two-component system regulates the virulence of Bordetella pertussis by controlling BvgS activity through the PAS domain. This mechanism may be generally applicable to other sensor histidine kinases with similar architectures.