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

Nature Communications
Kannan NatarajanNikolaos G Sgourakis

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.

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Citations

Dec 21, 2017·Annual Review of Immunology·Andrés AlcoverVincenzo Di Bartolo
Sep 10, 2019·PLoS Computational Biology·Bernhard KnappCharlotte M Deane
Sep 26, 2019·FEBS Letters·Flávio SádioGordana Wozniak-Knopp
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Dec 19, 2019·The Journal of Biological Chemistry·Roy A MariuzzaJohn Orban
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Methods Mentioned

BETA
NMR
surface plasmon resonance
X-ray
chip
size exclusion chromatography
transfection
ELISA
flow cytometry

Software Mentioned

NMRPipe
EVILFIT
Chimera
SEDFIT
NMRFAM
TALOS
T200
Molprobity
Phaser
DSSP

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