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

• Published in: Science (American Association for the Advancement of Science) Vol. 330; no. 6006; pp. 974 - 980
• Main Authors: Waldo, Gary L., Ricks, Tiffany K., Hicks, Stephanie N., Cheever, Matthew L., Kawano, Takeharu, Tsuboi, Kazuhito, Wang, Xiaoyue, Montell, Craig, Kozasa, Tohru, Sondek, John, Harden, T. Kendall
• Format: Journal Article
• Language: English
• Published: 12-11-2010
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1193438

Reciprocal Regulation
An essential step in many signaling cascades is inositol lipid hydrolysis catalyzed by phospholipase C–β. The latter is activated by the α subunit of the heterotrimeric G protein Gq, and it in turn inactivates Gαq, thus sharpening the signal.
Waldo
et al.
(p.
974
, published online 21 October) report structural and biochemical data that explain the basis of this reciprocal regulation. One domain of phospholipase C–β binds to activated Gαq. Though the phospholipase C–β active site remains occluded in the structure, the plug is probably removed upon G protein–dependent orientation of the lipase at the membrane. A second domain of phospholipase C–β accelerates guanosine triphosphate hydrolysis by Gαq causing the signaling complex to dissociate.
A crystal structure shows how the two components of a central signaling complex regulate each other.
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-βs and in turn are deactivated by these downstream effectors. The 2.7-angstrom structure of PLC-β3 bound to activated Gα
q
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 guanosine triphosphate hydrolysis by Gα
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.