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

Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Science (Impact Factor: 31.48). 11/2010; 330(6006):974-980. DOI: 10.1126/science.1193438

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.

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Available from: Stephanie N Hicks, Mar 12, 2015
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    • "PLC-ε is regulated directly by small GTPases of the Ras and Rho families, as well as subunits of G proteins (Bunney et al., 2006; Harden et al., 2009; Harden and Sondek, 2006). Crystal structures of human PLC-b3 (enzyme core or full-length) in complex with Gaq were recently solved, revealing novel structural insights into the function of each domain involved in Gaq-induced activation of PLC-b3 (Lyon et al., 2013, Waldo et al., 2010). Structure and regulation of PLC by GPCRs and other means have been recently reviewed (Gresset et al., 2012; Kadamur and Ross, 2013). "
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