Kinetic Scaffolding Mediated by a Phospholipase C-β and Gq 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: Washington, DC American Association for the Advancement of Science 12.11.2010
• Subjects: Activated; Amino Acid Sequence; Animals; Biological and medical sciences; Catalytic Domain; Cell physiology; Crystallography, X-Ray; Delay; Effectors; Enzyme Activation; Fundamental and applied biological sciences. Psychology; GTP-Binding Protein alpha Subunits, Gq-G11 - chemistry; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Guanosine Triphosphate - metabolism; Guanosines; Humans; Hydrogen Bonding; Hydrolysis; Isoenzymes - chemistry; Isoenzymes - metabolism; Kinetics; Mice; Models, Molecular; Molecular and cellular biology; Molecular biophysics; Molecular Sequence Data; Mutagenesis; Phospholipase; Phospholipase C beta - chemistry; Phospholipase C beta - metabolism; Protein Binding; Protein Structure, Tertiary; Proteins; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Signal Transduction; Stimuli; Structure in molecular biology; Tridimensional structure; Binding protein; Signal transduction; Three dimensional structure; Enzyme; Hydrolases; Esterases; Molecular complex; Phosphoric diester hydrolases; Kinetics; Protein; Phospholipase C; G protein
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1193438

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.