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

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Science  21 Oct 2010:
1193438
DOI: 10.1126/science.1193438

Abstract

Transmembrane signals initiated by a broad range of extracellular stimuli converge on nodes that regulate phospholipase C–dependent inositol lipid hydrolysis for signal propagation. Here, we describe how G proteins activate phospholipase C-βs and in turn are deactivated by these downstream effectors. The 2.7 Å structure of PLC-β3 bound to activated Gαq reveals a conserved module found within PLC-βs and other effectors optimized for rapid engagement of activated G proteins. The active site of PLC-β3 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-β3 subsequently accelerates GTP hydrolysis by Gαq 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.