9yap
Gbg crosslinked to PLCb3 - second conformation
Structural highlights
FunctionPLCB3_HUMAN The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes. Publication Abstract from PubMedPhospholipase C beta (PLCbeta) enzymes are activated by heterotrimeric G protein subunits, increasing hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) at the plasma membrane. All four human PLCbeta isoforms (PLCbeta1-4) are activated by Galpha(q), while PLCbeta1-3 are activated to varying extents by Gbetagamma. The binding sites for Galpha(q) on PLCbeta are well-established and much has been learned about its mechanism of activation, but comparatively little is known about Gbetagamma-dependent activation. In this work, we used cryo-electron microscopy (cryo-EM) single particle analysis (SPA), functional assays, and bioluminescence resonance energy transfer (BRET) to investigate how Gbetagamma interacts with PLCbeta3 in concert with activated Galpha(q) to regulate phospholipase activity. Gbetagamma heterodimers bind multiple surfaces of PLCbeta3 to promote activation but alone do not recruit the enzyme to the plasma membrane. Instead, Gbetagamma facilitates activation by Galpha(q), most likely by reorienting the phospholipase catalytic site at the membrane to maximize PIP2 hydrolysis and downstream Ca(2+) release. Cell-based functional assays demonstrate that Gbetagamma is required for maximal PLCbeta3 activation even when G(q) heterotrimers are the sole source of Gbetagamma. Together, these findings demonstrate that Gbetagamma acts as a critical positive allosteric modulator that regularly acts in concert with Galpha(q) to activate PLCbeta3 at the plasma membrane. Gbetagamma engages PLCbeta3 at multiple sites to reorient and facilitate its activation.,Fisher IJ, Senarath K, Outlaw K, Muralidharan K, Garland-Kuntz EE, Van Camp M, Komay T, Inoue A, Kostenis E, Lambert NA, Lyon AM bioRxiv [Preprint]. 2026 Jan 14:2026.01.14.699417. doi: , 10.64898/2026.01.14.699417. PMID:41648476[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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