Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, United States; R L Juliano Structural Bioinformatics Core Facility, The University of North Carolina at Chapel Hill, Chapel Hill, United States
Weigang Huang
Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, United States
Qisheng Zhang
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States; Division of Chemical Biology and Medicinal Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, United States; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States
T Kendall Harden
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, United States; Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, United States; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States
Direct activation of the human phospholipase C-γ isozymes (PLC-γ1, -γ2) 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-γ1 and PLC-γ2 is implicated in inflammation, autoimmunity, and cancer. Although structures of isolated domains from PLC-γ 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-γ 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-γ isozymes found in several cancers have a wide spectrum of activities, and highlights how these activities are tuned during disease.
