Protein Kinase C (PKC) is positively regulated by events that increase the plasma membrane concentration of diacylglycerol (DAG). Activation of PKC requires the coordinated binding of two membrane-targeting domains. The C1 domain binds diacylglycerol, the C2 domain binds phosphatidylserine. Each can bind the membrane independently, but with insufficient affinity for membrane recruitment and activation. The conventional Protein Kinase C (cPKC) isoforms have two membrane-targetting domains, a C1 domain which binds to the membrane lipid diacylglycerol (DAG) and a C2 domain which binds membrane phospholipids such as phosphatidylserine, in a calcium-dependent manner. Association of both domains with the plasma membrane produces a conformational change that releases an autoinhibitory pseudosubstrate segment from the substrate-binding cavity, allowing substrate binding and downstream signaling.