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The mechanism of Gα q regulation of PLCβ3 -catalyzed PIP2 hydrolysis.
bioRxiv 2023 August 31
UNLABELLED: PLCβ enzymes cleave PIP2 producing IP3 and DAG. 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. PLCβ enzymes are under the control of GPCR signaling through direct interactions with G proteins Gβγ and Gα q and have been shown to be coincidence detectors for dual stimulation of Gα q and G α i coupled receptors. PLCβs 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 Gβγ activates PLCβ3 by recruiting it to the membrane. Using these same methods, here we show that Gα q increases the catalytic rate constant, k cat , of PLCβ3 . Since stimulation of PLCβ3 by Gα q depends on an autoinhibitory element (the X-Y linker), we propose that Gα q produces partial relief of the X-Y linker autoinhibition through an allosteric mechanism. We also determined membrane-bound structures of the PLCβ3-Gα q , and PLCβ3-Gβγ(2)-Gα q complexes, which show that these G proteins can bind simultaneously and independently of each other to regulate PLCβ3 activity. The structures rationalize a finding in the enzyme assay, that co-stimulation by both G proteins follows a product rule of each independent stimulus. We conclude that baseline activity of PLCβ3 is strongly suppressed, but the effect of G proteins, especially acting together, provides a robust stimulus upon G protein stimulation.
SIGNIFICANCE STATEMENT: For certain cellular signaling processes, the background activity of signaling enzymes must be minimal and stimulus-dependent activation robust. Nowhere is this truer than in signaling by PLCβ3 , whose activity regulates intracellular Ca 2+ , phosphorylation by Protein Kinase C, and the activity of numerous ion channels and membrane receptors. In this study we show how PLCβ3 enzymes are regulated by two kinds of G proteins, Gβγ and Gα q . Enzyme activity studies and structures on membranes show how these G proteins act by separate, independent mechanisms, leading to a product rule of co-stimulation when they act together. The findings explain how cells achieve robust stimulation of PLCβ3 in the setting of very low background activity, properties essential to cell health and survival.
SIGNIFICANCE STATEMENT: For certain cellular signaling processes, the background activity of signaling enzymes must be minimal and stimulus-dependent activation robust. Nowhere is this truer than in signaling by PLCβ3 , whose activity regulates intracellular Ca 2+ , phosphorylation by Protein Kinase C, and the activity of numerous ion channels and membrane receptors. In this study we show how PLCβ3 enzymes are regulated by two kinds of G proteins, Gβγ and Gα q . Enzyme activity studies and structures on membranes show how these G proteins act by separate, independent mechanisms, leading to a product rule of co-stimulation when they act together. The findings explain how cells achieve robust stimulation of PLCβ3 in the setting of very low background activity, properties essential to cell health and survival.
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