FIG 7.

Flux-sensory model of the S. epidermidis five-component CAMP resistance system. In this model, GraS loads CAMPs onto the negatively charged 9-residue EL either directly from the membrane (solid arrow) or from the environment (dashed arrow). GraS would then interact with VraG, and the presence of the CAMP on GraS would dislodge the GL of VraG, leading to activation of the VraG efflux function. Presumably, once efflux is activated, this conformational change in VraG may be transmitted to GraS and lead to autophosphorylation of GraS. The activation of GraS then leads to phosphorylation of GraR and upregulation of downstream targets necessary for cell envelope modifications and CAMP resistance. Therefore, the primary functions of GraS and VraG are dependent on and inseparable from each other. GraS is the true sensor of the system but relies on the efflux function of VraG to activate, while concurrently VraG relies on GraS to efficiently present substrate for efflux. In such an arrangement, GraS and VraG can tightly regulate potentially deleterious modifications to the cell envelope in situations where it is absolutely essential for survival.