Two major regulators of virulence –Agr and Sae – are two component signal  transduction systems that rely on a membrane-embedded kinase and a DNA-binding protein to activate transcription initiation at virulence gene promoters. The membrane kinases are triggered by specific, extracellular signals (cell density for Agr, cationic antimicrobial peptides released by neutrophils for Sae). We discovered recently that the kinases for Sae and Agr are sensitive to the membrane lipid composition. Specifically, we found that the kinases require the wedge-shaped double phosopholipid cardiolipin and phospholipids containing branched-chain fatty acids (BCFAs) derived from isoleucine and valine to promote activity. The global regulator CodY triggers the Sae system by increasing the abundance of BCFAs in the membrane.  What are the roles for these fatty acids? Do they bind directly to the kinase? Or do they act indirectly by promoting diffusion of proteins within the plane of the membrane to affect activity? We are teaming up with the Gupta lab at Yale University to probe direct effects on BCFAs, and building tools to identify protein-protein interactions that are BCFA-dependent.