1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Structural basis for the activation of PLC-γ isozymes by phosphorylation and cancer-associated mutations

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Cite this article as: eLife 2019;8:e51700 doi: 10.7554/eLife.51700

Abstract

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.

Article and author information

Author details

  1. Nicole Hajicek

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7457-4830
  2. Nicholas C Keith

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  3. Edhriz Siraliev-Perez

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  4. Brenda R S Temple

    R L Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9233-0191
  5. Weigang Huang

    Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  6. Qisheng Zhang

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  7. T Kendall Harden

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    No competing interests declared.
  8. John Sondek

    Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    sondek@med.unc.edu
    Competing interests
    John Sondek, partial ownership of KXTbio, Inc. which licenses the production of WH-15.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1127-8310

Funding

National Institutes of Health (R01-GM057391)

  • John Sondek

National Institutes of Health (R01-GM098894)

  • Qisheng Zhang
  • John Sondek

National Science Foundation (DGE-1650116)

  • Edhriz Siraliev-Perez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Neel Shah

Publication history

  1. Received: September 6, 2019
  2. Accepted: December 30, 2019
  3. Accepted Manuscript published: December 31, 2019 (version 1)

Copyright

© 2019, Hajicek et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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