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.
- John Sondek
- Qisheng Zhang
- John Sondek
- Edhriz Siraliev-Perez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Neel Shah
- Received: September 6, 2019
- Accepted: December 30, 2019
- Accepted Manuscript published: December 31, 2019 (version 1)
© 2019, Hajicek et al.
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