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An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role

Author

Listed:
  • Kannan Natarajan

    (Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Andrew C. McShan

    (University of California Santa Cruz)

  • Jiansheng Jiang

    (Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Vlad K Kumirov

    (University of California Santa Cruz)

  • Rui Wang

    (Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Huaying Zhao

    (Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health)

  • Peter Schuck

    (Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health)

  • Mulualem E. Tilahun

    (Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Lisa F. Boyd

    (Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Jinfa Ying

    (Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • Ad Bax

    (Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • David H. Margulies

    (Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health)

  • Nikolaos G. Sgourakis

    (University of California Santa Cruz)

Abstract

The molecular mechanism through which the interaction of a clonotypic αβ T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood. Here we exploit a high-affinity TCR (B4.2.3) to examine the structural changes that accompany binding to its p/MHC ligand (P18-I10/H2-Dd). In addition to conformational changes in complementarity-determining regions (CDRs) of the TCR seen in comparison of unliganded and bound X-ray structures, NMR characterization of the TCR β-chain dynamics reveals significant chemical shift effects in sites removed from the MHC-binding site. Remodelling of electrostatic interactions near the Cβ H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests a possible role for an allosteric mechanism in TCR signalling. The contribution of these TCR residues to signal transduction is supported by mutagenesis and T-cell functional assays.

Suggested Citation

  • Kannan Natarajan & Andrew C. McShan & Jiansheng Jiang & Vlad K Kumirov & Rui Wang & Huaying Zhao & Peter Schuck & Mulualem E. Tilahun & Lisa F. Boyd & Jinfa Ying & Ad Bax & David H. Margulies & Nikola, 2017. "An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15260
    DOI: 10.1038/ncomms15260
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    Cited by:

    1. Jiansheng Jiang & Daniel K. Taylor & Ellen J. Kim & Lisa F. Boyd & Javeed Ahmad & Michael G. Mage & Hau V. Truong & Claire H. Woodward & Nikolaos G. Sgourakis & Peter Cresswell & David H. Margulies & , 2022. "Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Andrew C. McShan & David Flores-Solis & Yi Sun & Samuel E. Garfinkle & Jugmohit S. Toor & Michael C. Young & Nikolaos G. Sgourakis, 2023. "Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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