Kinetic scaffolding mediated by a phospholipase C-β and Gq signaling complex

Gary L. Waldo, Tiffany K. Ricks, Stephanie N. Hicks, Matthew L. Cheever, Takeharu Kawano, Kazuhito Tsuboi, Xiaoyue Wang, Craig Montell, Tohru Kozasa, John Sondek, T. Kendall Harden

Research output: Contribution to journalArticlepeer-review

Abstract

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 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 guanosine triphosphate 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.

Original languageEnglish (US)
Pages (from-to)974-980
Number of pages7
JournalScience
Volume330
Issue number6006
DOIs
StatePublished - Nov 12 2010

ASJC Scopus subject areas

  • General

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