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Science 330 (6006): 974-980

Copyright © 2010 by the American Association for the Advancement of Science

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

Gary L. Waldo,1 Tiffany K. Ricks,1 Stephanie N. Hicks,1 Matthew L. Cheever,1 Takeharu Kawano,2 Kazuhito Tsuboi,2 Xiaoyue Wang,3 Craig Montell,3 Tohru Kozasa,2,4 John Sondek,1,5,6 T. Kendall Harden1,6,*

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 G{alpha}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 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.

1 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
2 Department of Pharmacology, University of Illinois, Chicago, IL 60612, USA.
3 Departments of Biological Chemistry and Neuroscience, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
5 Department of Biochemistry, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
6 Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

* To whom correspondence should be addressed. E-mail: tkh{at}med.unc.edu


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