The correlation between multidomain enzymes and multiple activation mechanisms- The case of phospholipase Cβ and its membrane interactions

► We review the domain organization of phospholipase Cb and relate this to modes of activation. ► We suggest how binding of PLCβ2 at the membrane surface through its PH domain induces activation. ► We discuss the role of the insertion loop as a model for activation. ► We present a comprehensive structure-based model of PLCβ2 activation states at the membrane. ► We discuss future challenges in the regulation of PLCβ enzymes in cellular settings.