Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations.

Nicole Hajicek, Nicholas C Keith, Edhriz Siraliev-Perez, Brenda Rs Temple, Weigang Huang, Qisheng Zhang, T Kendall Harden, John Sondek

eLife 2019 Dec 31

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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. © 2019, Hajicek et al.

Citation

Nicole Hajicek, Nicholas C Keith, Edhriz Siraliev-Perez, Brenda Rs Temple, Weigang Huang, Qisheng Zhang, T Kendall Harden, John Sondek. Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations. eLife. 2019 Dec 31;8