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

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 () and Nikolaos G. Sgourakis ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15260

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