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Cited by 89Protein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancerProtein Tyrosine Phosphatases

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

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Hajicek, Nicole, Keith, Nicholas C, Siraliev-Perez, Edhriz, Temple, Brenda RS, Huang, Weigang, Zhang, Qisheng, Harden, T Kendall, Sondek, John·2019·eLife
DOI 10.7554/elife.51700PMC PMC7004563
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Abstract

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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Crossref · 10.7554/elife.51700

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  • In AD, the effect of PLCG2 might depend on the stage of neurodegeneration, the gene expression, the enzymatic activity, and the formation of intracellular signaling complexes in microglia.

    “In AD, the effect of PLCG2 might depend on the stage of neurodegeneration, the gene expression, the enzymatic activity, and the formation of intracellular signaling complexes in microglia [10, 13–16].”

    From PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease (2022) · cites this paper as [14]

    The Introduction links a moderately active PLC-γ2 variant to protection from late-onset Alzheimer’s disease, supporting a possible role for enzymatic activity. It also describes PLC-γ domains that scaffold signaling proteins, but neither the Introduction nor the Discussion says that PLCG2’s effect in Alzheimer’s depends on neurodegeneration stage, gene expression, or signaling-complex formation in microglia. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Following phosphorylation of PLCγ1, the critical pTyr residue binds to its cSH2 domain, and this intramolecular interaction is required for repositioning of the regulatory region and release of autoinhibition.

    “Following phosphorylation of PLCγ1, the critical pTyr residue in PLCγ1 binds to its cSH2 domain; this intramolecular interaction is required for repositioning of the regulatory region and release of the autoinhibition.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [47]

    The Results (Structure of full-length PLC-γ1; page not provided) describe pTyr783 as an intramolecular ligand for cSH2. The Discussion (page not provided) proposes that this engagement unlatches cSH2 and initiates regulatory-domain rearrangement, but calls that mechanism presumed rather than establishing that the interaction is required for rearrangement and release of autoinhibition. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PLCγ1 shares 52% sequence identity with PLCγ2, and their overall domain organisation is conserved; therefore, homology models are plausible.

    “PLCγ1 shares 52% sequence identity with PLCγ2, and their overall domain organisation is conserved; therefore, homology models are plausible.”

    From Characterisation of molecular mechanisms for PLCγ2 disease-linked variants (2024) · cites this paper as Hajicek et al., 2019

    The Results section, “Structure of full-length PLC-γ1” (page unavailable), describes domains shared by the PLC-γ isozymes. The Materials and methods section, “Homology modeling” (page unavailable), reports building a PLC-γ2 model from a PLC-γ1 template. Our copy does not substantiate the specific figure of 52% sequence identity. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In inactive PLCγ1, cSH2 and sPH domains contribute to autoinhibition by interacting with the PLC-core, preventing membrane interactions required for access to PI(4,5)P2.

    “In the inactive form, two domains within the regulatory region (cSH2 and sPH) directly contribute to autoinhibition by interacting with the PLC-core, preventing membrane interactions required for the access to the PLC substrate, PI(4,5)P2 [47,48].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [47]

  • There are currently no structures for the full-length PLCγ2 molecule, but useful information can be inferred from the recently-published crystal and cryo-electron microscopy (cryoEM) structures of the closely related PLCγ1 molecule.

    “Conversely, there are currently no structures for the full-length PLCγ2 molecule, but we can infer some useful information from the recently-published crystal and cryo-electron microscopy (cryoEM) structures of the closely related PLCγ1 molecule [83, 84].”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [83]

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Cited by

Sorted by citations

Authors
Hajicek, N., Keith, N. C., Siraliev-Perez, E., Temple, B. R., Huang, W., Zhang, Q., Harden, T. K., & Sondek, J.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Sondek, John
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2019-12-31
Volume
8
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.51700
PMC
PMC7004563
OpenAlex
W4252787894
Cited by
89
References
15
Citations by year
2026: 9 · 2025: 16 · 2024: 18 · 2023: 16 · 2022: 12 · 2021: 10 · 2020: 7 · 2019: 1
FWCI
2.48
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01-GM057391, R01-GM098894)
  • National Science Foundation (DGE-1650116)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
phospholipase C-gamma, PLCγ1, PLCγ2, tyrosine phosphorylation, enzyme activation, allosteric regulation, cancer-associated mutations, full-length protein structure

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