TCR binding to a peptide-MHC complex raises a drawbridge for CD3 cross-membrane signaling

Abstract

In this study, we present an allosteric mechanism for T cell receptor (TCR) triggering upon binding a peptide-MHC complex (pMHC), in which a conformational change in the TCR upon pMHC binding controls the mobility of the CD3 proteins. We found that the TCR{beta} FG loop serves as a gatekeeper, preventing accidental triggering, while the connecting peptide acts as a hinge for essential conformational changes in the TCR. Atomistic simulations and cell-based experiments with genetically modified connecting peptides demonstrate that rigidified hinge residues result in excessive CD3 dynamics and hypersensitivity to pMHC binding. Our model thus provides a clear connection between extracellular TCR-pMHC binding and changes in CD3 dynamic that propagate from outside to inside the cell.