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All four human PLC\u03b2 isoforms (PLC\u03b21\u20134) are activated by G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    , whereas PLC\u03b21\u20133 are activated to varying extents by G\u03b2\u03b3. The binding sites for G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    on PLC\u03b2 are well established, and much has been learned about its mechanism of activation, but comparatively little is known about G\u03b2\u03b3-dependent activation. In this work, we used cryo-electron microscopy single-particle analysis, functional assays, and bioluminescence resonance energy transfer to investigate how G\u03b2\u03b3 interacts with PLC\u03b23 in concert with activated G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    to regulate phospholipase activity. G\u03b2\u03b3 heterodimers bind multiple surfaces of PLC\u03b23 to promote activation, but alone do not recruit the enzyme to the plasma membrane. Instead, G\u03b2\u03b3 facilitates activation by G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    , most likely by reorienting the phospholipase catalytic site at the membrane to maximize PI(4,5)P2 hydrolysis and downstream Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release. Cell-based functional assays demonstrate that G\u03b2\u03b3 is required for maximal PLC\u03b23 activation, even when G\n                    <jats:sub>q<\/jats:sub>\n                    heterotrimers are the sole source of G\u03b2\u03b3. Together, these findings demonstrate that G\u03b2\u03b3 acts as a critical positive allosteric modulator that regularly acts in concert with G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    to activate PLC\u03b23 at the plasma membrane.\n                  <\/jats:p>","DOI":"10.7554\/elife.110382","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T14:30:47Z","timestamp":1775831447000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110382","source":"Crossref","is-referenced-by-count":2,"title":["G\u03b2\u03b3 engages PLC\u03b23 at multiple sites to reorient and facilitate its activation"],"prefix":"10.7554","volume":"15","author":[{"given":"Isaac J","family":"Fisher","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dqehb95","id-type":"ROR","asserted-by":"publisher"}],"name":"James Tarpo Jr. and Margaret Tarpo Department of Chemistry, Purdue University","place":["West Lafayette, United 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