Kinetic Scaffolding Mediated by a Phospholipase C-β and Gq Signaling Complex

Transmembrane signals initiated by a broad range of extracellular stimuli converge on nodes that regulate phospholipase C (PLC)-dependent inositol lipid hydrolysis for signal propagation. We describe how heterotrimeric guanine nucleotide-binding proteins (G proteins) activate PLC-beta s and in turn are deactivated by these downstream effectors. The 2.7-angstrom structure of PLC-beta 3 bound to activated G alpha(q) reveals a conserved module found within PLC-beta s and other effectors optimized for rapid engagement of activated G proteins. The active site of PLC-beta 3 in the complex is occluded by an intramolecular plug that is likely removed upon G protein-dependent anchoring and orientation of the lipase at membrane surfaces. A second domain of PLC-beta 3 subsequently accelerates guanosine triphosphate hydrolysis by G alpha(q), causing the complex to dissociate and terminate signal propagation. Mutations within this domain dramatically delay signal termination in vitro and in vivo. Consequently, this work suggests a dynamic catch-and-release mechanism used to sharpen spatiotemporal signals mediated by diverse sensory inputs.