Full-Length Gαq–Phospholipase C-β3 Structure Reveals Interfaces of the C-terminal Coiled-Coil Domain

Phospholipase C-β (PLCβ) is directly activated by Gαq, but the molecular basis for how its distal C-terminal domain (CTD) contributes to maximal activity is poorly understood. Herein we present both the crystal structure and cryo-EM 3D reconstructions of human full-length PLCβ3 in complex with murine Gαq. The distal CTD forms an extended, monomeric helical bundle consisting of three anti-parallel segments with structural similarity to membrane-binding bin–amphiphysin–Rvs (BAR) domains. Sequence conservation of the distal CTD identifies putative membrane and protein interaction sites, the latter of which bind the N-terminal helix of Gαq in both the crystal structure and cryo-EM reconstructions. Functional analysis suggests the distal CTD plays roles in membrane targeting and in optimizing the orientation of the catalytic core at the membrane for maximal rates of lipid hydrolysis. Phospholipase C (PLC) isozymes hydrolyze the inner membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2) to generate the second messengers diacylglycerol and inositol 1,4,5-triphosphate (IP3), which in turn promote the release of intracellular calcium and activate protein kinase C (PKC)1,2. Among the PLC subfamilies