Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complex.
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.
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Gary L
GL
Waldo
Tiffany K
TK
Ricks
Stephanie N
SN
Hicks
Matthew L
ML
Cheever
Takeharu
T
Kawano
Kazuhito
K
Tsuboi
Xiaoyue
X
Wang
Craig
C
Montell
Tohru
T
Kozasa
John
J
Sondek
T Kendall
TK
Harden
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry* / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D054799:Phospholipase C beta / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D006160:Guanosine Triphosphate; C518039:PLCB3 protein, human; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11