8uqn | pdb_00008uqn
PLCb3-Gaq complex on membranes
Structural highlights
DiseaseGNAQ_HUMAN Sturge-Weber syndrome;Phakomatosis cesioflammea;Uveal melanoma;Familial multiple nevi flammei. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGNAQ_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro) (By similarity). Publication Abstract from PubMedPLCbeta (Phospholipase Cbeta) enzymes cleave phosphatidylinositol 4,5-bisphosphate (PIP2) producing IP3 and DAG (diacylglycerol). PIP2 modulates the function of many ion channels, while IP3 and DAG regulate intracellular Ca(2+) levels and protein phosphorylation by protein kinase C, respectively. PLCbeta enzymes are under the control of G protein coupled receptor signaling through direct interactions with G proteins Gbetagamma and Galpha(q) and have been shown to be coincidence detectors for dual stimulation of Galpha(q) and Galpha(i)-coupled receptors. PLCbetas are aqueous-soluble cytoplasmic enzymes but partition onto the membrane surface to access their lipid substrate, complicating their functional and structural characterization. Using newly developed methods, we recently showed that Gbetagamma activates PLCbeta3 by recruiting it to the membrane. Using these same methods, here we show that Galpha(q) increases the catalytic rate constant, k(cat), of PLCbeta3. Since stimulation of PLCbeta3 by Galpha(q) depends on an autoinhibitory element (the X-Y linker), we propose that Galpha(q) produces partial relief of the X-Y linker autoinhibition through an allosteric mechanism. We also determined membrane-bound structures of the PLCbeta3.Galpha(q) and PLCbeta3.Gbetagamma(2).Galpha(q) complexes, which show that these G proteins can bind simultaneously and independently of each other to regulate PLCbeta3 activity. The structures rationalize a finding in the enzyme assay, that costimulation by both G proteins follows a product rule of each independent stimulus. We conclude that baseline activity of PLCbeta3 is strongly suppressed, but the effect of G proteins, especially acting together, provides a robust stimulus upon G protein stimulation. The mechanism of Galpha(q) regulation of PLCbeta3-catalyzed PIP2 hydrolysis.,Falzone ME, MacKinnon R Proc Natl Acad Sci U S A. 2023 Nov 28;120(48):e2315011120. doi: , 10.1073/pnas.2315011120. Epub 2023 Nov 22. PMID:37991948[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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