Descriptions

PLCε is a critical regulator of calcium and DAG-dependent signaling in the cardiovascular system, where changes in its expression and/or aberrant activation result in cardiac hypertrophy and heart failure. PLCε shares four core domains common to most PLCs, including a pleckstrin homology (PH) domain, followed by four tandem EF hand repeats (EF1-4), the catalytic TIM barrel domain (split by an autoregulatory X-Y linker), and a C2 domain. In PLCε, these core domains are flanked by regions that confer responsiveness to different signal transduction pathways. The N-terminal region contains a CDC25 domain that acts as a guanine nucleotide exchange factor (GEF) for the Rap1A GTPase. This domain is essential for sustained PI hydrolysis at the perinuclear and Golgi membranes in cardiomyocytes. The C-terminal region contains two Ras association (RA) domains (RA1 and RA2) that bind activated Rap1A and Ras. PLCε is present predominantly in the cytoplasm, and is maintained in a low-activity state by the autoinhibitory X-Y linker and the C2-RA1 linker. Localization of PLCε to the perinuclear membrane through interactions between the RA1 domain and the scaffolding protein mAKAP increases lipase activity. RA1 binding to mAKAP could alter the conformation of, or displace, the C2-RA1 linker, increasing basal activity. Membrane association would also increase basal activity via interfacial activation, which may be facilitated by interactions between the αx-y helix and the membrane or, alternatively, with other domain in PLCε or proteins at the target membrane, such as activated Rap1A.

Accessory elements