TY - JOUR TI - Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations AU - Hajicek, Nicole AU - Keith, Nicholas C AU - Siraliev-Perez, Edhriz AU - Temple, Brenda RS AU - Huang, Weigang AU - Zhang, Qisheng AU - Harden, T Kendall AU - Sondek, John A2 - Shah, Neel A2 - Kuriyan, John A2 - Shah, Neel A2 - Gierschik, Peter VL - 8 PY - 2019 DA - 2019/12/31 SP - e51700 C1 - eLife 2019;8:e51700 DO - 10.7554/eLife.51700 UR - https://doi.org/10.7554/eLife.51700 AB - 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. KW - phospholipase C KW - allostery KW - interfacial regulation KW - X-ray crystallography KW - molecular dynamics KW - cancer JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -