{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:53:10Z","timestamp":1785840790988,"version":"3.56.0"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"48","license":[{"start":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T00:00:00Z","timestamp":1700611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["HHMI"],"award-info":[{"award-number":["HHMI"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5F32GM142137-03"],"award-info":[{"award-number":["5F32GM142137-03"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,11,28]]},"abstract":"\n PLC\u03b2<\/jats:italic>\n (\n Phospholipase C\u03b2<\/jats:italic>\n ) enzymes cleave phosphatidylinositol 4,5-bisphosphate (\n PIP2)<\/jats:italic>\n producing\n IP3<\/jats:italic>\n and\n DAG<\/jats:italic>\n (diacylglycerol).\n PIP2<\/jats:italic>\n modulates the function of many ion channels, while\n IP3<\/jats:italic>\n and\n DAG<\/jats:italic>\n regulate intracellular Ca\n 2+<\/jats:sup>\n levels and protein phosphorylation by protein kinase C, respectively.\n PLC\u03b2<\/jats:italic>\n enzymes are under the control of G protein coupled receptor signaling through direct interactions with G proteins\n G\u03b2\u03b3<\/jats:italic>\n and\n \n G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n and have been shown to be coincidence detectors for dual stimulation of\n \n G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n and\n G\u03b1<\/jats:italic>\n \n i<\/jats:italic>\n <\/jats:sub>\n -coupled receptors.\n PLC\u03b2s<\/jats:italic>\n are aqueous-soluble cytoplasmic enzymes but partition onto the membrane surface to access their lipid substrate, complicating their functional and structural characterization. Using newly developed methods, we recently showed that\n G\u03b2\u03b3<\/jats:italic>\n activates\n PLC\u03b23<\/jats:italic>\n by recruiting it to the membrane. Using these same methods, here we show that\n \n G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n increases the catalytic rate constant,\n \n k\n cat<\/jats:sub>\n <\/jats:italic>\n , of\n PLC\u03b23<\/jats:italic>\n . Since stimulation of\n PLC\u03b23<\/jats:italic>\n by\n \n G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n depends on an autoinhibitory element (the X-Y linker), we propose that\n \n G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n produces partial relief of the X-Y linker autoinhibition through an allosteric mechanism. We also determined membrane-bound structures of the\n \n PLC\u03b23\u00b7G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n and\n PLC\u03b23\u00b7G\u03b2\u03b3<\/jats:italic>\n (2)<\/jats:italic>\n \n \u00b7G\u03b1\n q<\/jats:sub>\n <\/jats:italic>\n complexes, which show that these G proteins can bind simultaneously and independently of each other to regulate\n PLC\u03b23<\/jats:italic>\n activity. The structures rationalize a finding in the enzyme assay, that costimulation by both G proteins follows a product rule of each independent stimulus. We conclude that baseline activity of\n PLC\u03b23<\/jats:italic>\n is strongly suppressed, but the effect of G proteins, especially acting together, provides a robust stimulus upon G protein stimulation.\n <\/jats:p>","DOI":"10.1073\/pnas.2315011120","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T12:47:36Z","timestamp":1700657256000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["The mechanism of\n \n G\u03b1\n q<\/sub>\n <\/i>\n regulation of\n PLC\u03b23<\/i>\n -catalyzed\n PIP2<\/i>\n hydrolysis"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6738-7017","authenticated-orcid":false,"given":"Maria E.","family":"Falzone","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10065"},{"name":"HHMI, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick","family":"MacKinnon","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10065"},{"name":"HHMI, The Rockefeller University, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,11,22]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj0630223"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj0790193"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2019.04.001"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2013.10.023"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2015.01.011"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183750"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.56.070187.001111"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.113.087403"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2014.10.008"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2497"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2095"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.06.018"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.586784"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2301121120"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.1.496"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1193438"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.198200"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800907200"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2010.06.013"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bej.2012.01.010"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2012.09.022"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002553"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000926"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.005291"},{"key":"e_1_3_4_25_2","first-page":"62","volume-title":"Methods in Enzymology","author":"White S. 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