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- W4377029095 abstract "<b>Abstract ID 23793</b> <b>Poster Board 164</b> G protein-coupled receptors (GPCRs) transduce extracellular stimuli into intracellular signaling events through activation of the heterotrimeric G protein subunits, Gα and Gβγ. G proteins in turn activate effector enzymes, such as phospholipase C β (PLCβ), to produce second messengers. The four human PLCβ isoforms (PLCb1-4) are all potently activated by direct binding of Gα<sub>q</sub>, but only PLCβ1-3 are also directly activated by Gβγ. Dysregulation of the G protein-phospholipase C signaling axis has been implicated in numerous pathologies and disease states. Direct inhibition of these pathways has shown therapeutic potential in models of inflammation, cardiac hypertrophy, opioid analgesia, and cancer. Much is known about how Gα<sub>q </sub>binds to and activates PLCβ, but despite decades of research, the molecular details of Gβγ-stimulated activation have been elusive. Using a protein engineering strategy and single particle cryo-electron microscopy, we have now determined high-resolution structures of functional Gβγ–PLCβ3 complexes. The structures reveal that the Gβγ interacts with PLCβ3 through multivalent interactions with the PH domain, EF hands and the C2 domains of PLCβ. The structures differ in the engagement of the Gβγ subunit with the PH-EF hand interface. Intriguingly, one conformation of the Gβγ–PLCβ complex is compatible with simultaneous binding of Gα<sub>i</sub>, which has not been observed for any other Gβγ–effector enzyme complex. Cellular activity assays suggest that this conformation is less sensitive to Gβγ-dependent activation, and, in assays with purified components, that crosslinked Gβγ-PLCβ complexes still sensitive to Gα<sub>i</sub> inhibition. Thus, Gβγ or the Gα<sub>i</sub>βγ complex may also function as a scaffold for PLCβ, in which a pre-activated complex is maintained at the membrane. Current efforts in the lab include investigating the scaffolding function of these complexes and PLCβ insensitivity to Gβγ activation." @default.
- W4377029095 created "2023-05-19" @default.
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- W4377029095 date "2023-05-18" @default.
- W4377029095 modified "2023-09-29" @default.
- W4377029095 title "Molecular mechanisms of Gβγ-stimulated activation of PLCβ" @default.
- W4377029095 doi "https://doi.org/10.1124/jpet.122.237930" @default.
- W4377029095 hasPublicationYear "2023" @default.
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