Structural Insights into Phospholipase Cε Function

Phospholipase Cε (PLCε) is a member of the PLC family of enzymes, which hydrolyze phosphatidylinositol lipids following the activation of G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). PLCε is unique among the PLC superfamily as it contains an N-terminal CDC25 domain, which has a guanine nucleotide exchange factor (GEF) activity for the small G protein Rap1A, and two C-terminal Ras association (RA) domains that bind scaffolding proteins and activated G proteins. PLCε activity plays an important role in cardiomyocyte contractility and survival. The best-characterized pathway of PLCε activation is mediated by β-adrenergic (β-AR) receptors. Stimulation of these receptors culminates in the activation of the small GTPase Rap1A, which binds to PLCε at the sarcoplasmic reticulum. There, PLCε hydrolyzes phosphatidylinol-4-phosphate (PI₄P) to produce diacylglycerol (DAG). Prolonged activation of this pathway results in increased Ca²⁺-induced Ca²⁺ release (CICR) and increased expression of hypertrophy-related genes. However, the structural basis of PLCε basal activity, and the mechanism of Rap1A activation are largely unknown. We have now obtained the first high-resolution structure of PLCε. These studies, together with biochemical validation of our structure-based hypotheses, provide the first molecular insights into this enzyme.