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

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

doi:10.7554/eLife.51700

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

Journal Article · 31 December 2019 · eLife

DOI: https://doi.org/10.7554/eLife.51700 · OSTI ID:1600781

^[1];

^[1]; Huang, Weigang ^[1]; Zhang, Qisheng ^[1]; Harden, T. Kendall ^[1];

^[1]

Univ. of North Carolina, Chapel Hill, NC (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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; National Science Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1600781

Journal Information:: eLife, Journal Name: eLife Journal Issue: 2019 Vol. 8; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Mesenchymal Chemotaxis Requires Selective Inactivation of Myosin II at the Leading Edge via a Noncanonical PLCγ/PKCα Pathway Anisur, Rahman,; E., Bear, James; J., King, Samantha The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/m06r-1438	text	January 2014
Membrane-induced Allosteric Control of Phospholipase C-β Isozymes H., Charpentier, Thomas; O., Barrett, Matthew; John, Sondek, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/m9k7-j936	text	January 2014
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease Sarah, Taylor,; David, Craig,; Liming, Qu, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/pbds-w495	text	January 2017
Mechanism of Phosphorylation-induced Activation of Phospholipase C-γ Isozymes Kendall, Harden, T.; Aurelie, Gresset,; John, Sondek, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/xnkc-9f07	text	January 2010
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Sims, Rebecca; Van Der Lee, Sven J.; Naj, Adam C. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.21667	text	January 2017
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard. Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. International Union of Crystallography (IUCr) https://doi.org/10.17863/cam.52329	journalarticle	January 2008
A New Tyrosine Phosphorylation Site in PLCγ1: The Role of Tyrosine 775 in Immune Receptor Signaling Serrano, Carmen J.; Graham, Laurie; DeBell, Karen The Journal of Immunology, Vol. 174, Issue 10 https://doi.org/10.4049/jimmunol.174.10.6233	journal	May 2005

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