A unique fold of phospholipase C-β mediates dimerization and interaction with Gαq

GTP-bound subunits of the Gq family of Gα subunits directly activate phospholipase C-β (PLC-β) isozymes to produce the second messengers inositol 1,4,5-trisphosphate and diacylglycerol. PLC-βs are GTPase activating proteins (GAPs) that also promote the formation of GDP-bound, inactive Gβ subunits. Both phospholipase activation by Gα–GTP subunits and GAP activity require a C-terminal region unique to PLC-β isozymes. The crystal structure of the C-terminal region from an avian PLC-β, determined at 2.4 Å resolution, reveals a novel fold composed almost entirely of three long helices forming a coiled-coil that dimerizes along its long axis in an antiparallel orientation. The dimer interface is extensive (∼3,200 Å2), and, based on gel exclusion chromatography, full length PLC-βs are dimeric, indicating that PLC-βs likely function as dimers. Sequence conservation, mutational data and molecular modeling show that an electrostatically positive surface of the dimer contains the major determinants for binding Gβq. Effector dimerization, as highlighted by PLC-βs, provides a viable mechanism for regulating signaling cascades linked to heterotrimeric G proteins.