6pbc

Publication Abstract from PubMed

Direct activation of the human phospholipase C-g isozymes (PLC-g1, -g2) 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-g1 and PLC-g2 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-g 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-g 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-g isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.

Structural basis for the activation of PLC-gamma isozymes by phosphorylation and cancer-associated mutations.,Hajicek N, Keith NC, Siraliev-Perez E, Temple BRS, Huang W, Zhang Q, Harden TK, Sondek J Elife. 2019 Dec 31;8. pii: 51700. doi: 10.7554/eLife.51700. PMID:31889510^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.