{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T18:37:01Z","timestamp":1793731021469,"version":"4.6.1"},"reference-count":92,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-GM057391"],"award-info":[{"award-number":["R01-GM057391"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-GM098894"],"award-info":[{"award-number":["R01-GM098894"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DGE-1650116"],"award-info":[{"award-number":["DGE-1650116"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Direct activation of the human phospholipase C-\u03b3 isozymes (PLC-\u03b31, -\u03b32) by tyrosine phosphorylation is fundamental to the control of diverse biological processes, including chemotaxis, platelet aggregation, and adaptive immunity. In turn, aberrant activation of PLC-\u03b31 and PLC-\u03b32 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-\u03b3 isozymes are available, these structures are insufficient to define how release of basal autoinhibition is coupled to phosphorylation-dependent enzyme activation. Here, we describe the first high-resolution structure of a full-length PLC-\u03b3 isozyme and use it to underpin a detailed model of their membrane-dependent regulation. Notably, an interlinked set of regulatory domains integrates basal autoinhibition, tyrosine kinase engagement, and additional scaffolding functions with the phosphorylation-dependent, allosteric control of phospholipase activation. The model also explains why mutant forms of the PLC-\u03b3 isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.<\/jats:p>","DOI":"10.7554\/elife.51700","type":"journal-article","created":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T08:00:12Z","timestamp":1577779212000},"source":"Crossref","is-referenced-by-count":87,"title":["Structural basis for the activation of PLC-\u03b3 isozymes by phosphorylation and cancer-associated mutations"],"prefix":"10.7554","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7457-4830","authenticated-orcid":true,"given":"Nicole","family":"Hajicek","sequence":"first","affiliation":[{"name":"Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4050-9261","authenticated-orcid":true,"given":"Nicholas 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