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Cited by 24Protein Kinase Regulation and GTPase SignalingT-cell and B-cell ImmunologyProtein Structure and Dynamics

Cooperative assembly of a four-molecule signaling complex formed upon T cell antigen receptor activation

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Manna, Asit, Zhao, Huaying, Wada, Junya, Balagopalan, Lakshmi, Tagad, Harichandra D., Appella, Ettore, Schuck, Peter, Samelson, Lawrence E.·2018·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1817142115PMC PMC6304999
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Abstract

Significance: An early event during cellular activation in many biologic systems is recruitment of the cytosolic enzyme phospholipase-Cγ1 to the plasma membrane where, on activation, it cleaves its lipid substrates into functional second messengers. T cell antigen receptor engagement during the immune response leads to rapid formation of a multiprotein complex that brings phospholipase-Cγ1 to the plasma membrane with three adapter molecules. We reconstituted this quaternary complex in vitro and used biophysical techniques to determine stoichiometry and measure the affinities of the interacting proteins and the energetics of formation. We observe cooperative formation of a circular loop of interactions associated with a significant entropic penalty facilitating reversibility. Such instability might be a target of regulation during T cell activation.

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Crossref · 10.1073/pnas.1817142115

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  • In T-cell signalling, several adaptor proteins are associated with activated PLCγ1, including LAT, SLP76 and GADS.

    “In the context of T-cell signalling, it is documented that several adaptor proteins are associated with activated PLCγ1, including LAT, SH2-domain-containing leukocyte protein of 76 kDa (SLP76) and GRB2-related adaptor downstream of Shc (GADS) [72].”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [72]

    The Discussion describes PLC-γ1 binding in a complex with LAT, Gads and SLP-76 after T-cell receptor engagement. The Abstract says this complex recruits PLC-γ1 to the membrane, where it is subsequently activated; it does not establish that the three adaptors are associated with PLC-γ1 after activation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The partner protein could be a RTK or a phosphotyrosine motif associated with an adaptor protein, such as LAT in T-cells, or BLNK in B-cells.

    “The partner protein could be a RTK [84, 88] or a phosphotyrosine motif associated with an adaptor protein, such as LAT in T-cells [72], or BLNK in B-cells [89].”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [72]

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Cited by

Sorted by citations

Authors
Manna, A., Zhao, H., Wada, J., Balagopalan, L., Tagad, H. D., Appella, E., Schuck, P., & Samelson, L. E.
Affiliations
  • National Cancer Institute (US)
  • National Institute of Biomedical Imaging and Bioengineering (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2018-12-03
Volume
115
Issue
51
Pages
E11914-E11923
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1817142115
PMC
PMC6304999
OpenAlex
W2902105821
Cited by
24
References
0
Citations by year
2026: 1 · 2025: 3 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 3
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 182 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
T cell receptor signaling, phospholipase C-gamma1, protein complex formation, adaptor proteins, phosphopeptides, enthalpy-entropy compensation, protein-protein interaction, T cell activation, inositol trisphosphate, diacylglycerol, protein kinase C, isothermal calorimetry, analytical ultracentrifugation
MeSH terms
Cell Membrane, Humans, Membrane Lipids, Membrane Proteins, Phosphoproteins, Phosphorylation, Tissue Plasminogen Activator, Protein Binding, Receptors, Antigen, T-Cell, Recombinant Proteins, Thermodynamics, Signal Transduction, Tumor Necrosis Factor Receptor Superfamily, Member 7, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Phospholipase C gamma, Protein Interaction Domains and Motifs

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