Activation of phospholipase C β by Gβγ and Gαq involves C-terminal rearrangement to release auto-inhibition

Phospholipase C (PLC) enzymes hydrolyse phosphoinositide lipids to inositol phosphates and diacylglycerol. Direct activation of PLC{beta} by Gq and/or G{beta}{gamma} subunits mediates signalling by Gq and some Gi coupled G protein-coupled receptors (GPCRs), respectively. PLC{beta} isoforms contain a unique C-terminal extension, consisting of proximal and distal C-terminal domains (CTD) separated by a flexible linker. The structure of PLC{beta}3 bound to Gq is known, however, for both Gq and G{beta}{gamma}, the mechanism for PLC{beta} activation on membranes is unknown. We examined PLC{beta}2 dynamics on membranes using hydrogen deuterium exchange mass spectrometry (HDX-MS). G{beta}{gamma} caused a robust increase in dynamics of the distal C-terminal domain (CTD). Gq showed decreased deuterium incorporation at the Gq binding site on PLC{beta}. In vitro G{beta}{gamma}-dependent activation of PLC is inhibited by the distal CTD. The results suggest that disruption of auto-inhibitory interactions with the CTD, respectively, leads to increased PLC{beta} hydrolase activity.