Understanding the Molecular Mechanism of PLCε Regulation and G Protein‐Mediated Activation

• DOI: 10.1096/fasebj.2022.36.s1.r3903
• Publication Date: 2022-05-03T08:23:48Z
• Authors: Kaushik Muralidharan; Rachel Tat; Kennedy Outlaw; Vaani Ohri; Hannah Flaherty; Elisabeth Garland...; Angeline Lyon
• Keywords: Gq alpha subunit; Pleckstrin homology domain; Small GTPase; Second messenger system

Cardiovascular disease is the leading cause of death in world. The phospholipase C (PLC) family enzymes, particular PLCε subfamily, are essential for normal cardiovascular function. hydrolyzes phosphatidylinositol phosphates at cellular membranes, producing inositol (IPx ) and diacylglycerol (DAG). These crucial secondary messengers activate multiple downstream pathways, including cardiac contractility expression hypertrophic genes. In system, regulated through direct interactions with RhoA Rap1A small GTPases, which turn activated G protein-coupled receptors (GPCRs). reported to plasma membrane, whereas translocates activates perinuclear membrane. However, elements within that regulate basal activity membrane association have not been fully identified. Similarly, domains involved versus binding, activation translocation different subcellular membranes mapped. this work, we use a structure-guided approach, together cell-based assays, epifluorescence, confocal microscopy identify roles regulatory activity, localization, regulation by GTPases. Functional studies show N- C-terminal dictate its location cell, contribute differently protein-dependent activity. We also insertions catalytic TIM barrel, X-Y linker Y-box, aid interfacial association. provide much needed insights into molecular determinants localization cells, critical elucidating