I-107 Long-range allosteric effects induced by Tax–HLA-A2 binding to an anti-HTLV-1 TCR: Implications for early T cell signaling

Abstract

The mechanism whereby αβ T cell receptor (TCR) engagement by peptide–MHC (pMHC) is first communicated to the CD3 signaling apparatus of the TCR–CD3 complex, a process termed early T cell activation, is not well understood. To address the possibility that pMHC binding induces allosteric changes in TCR conformation and/or dynamics that are relayed to CD3, we carried out NMR analysis and molecular dynamics (MD) simulations of both the α and β chains of a human antiviral TCR (A6) that recognizes the Tax antigen from HTLV-1 bound to HLA-A2. We observed pMHC-induced NMR signal perturbations in the TCR V domains that propagate to 3 distinct sites in the C domains: (1) the Cβ FG loop that projects from the Vβ/Cβ interface, (2) a cluster of Cβ residues near the Cβ αA helix, a region involved in interactions with CD3, and (3) the Cα AB loop located at the membrane-proximal base of the TCR. A biological role for each of these allosteric sites is supported by previous mutational and functional studies of TCR signaling. In addition, the pattern of long-range ligand-induced changes in TCR A6 seen by NMR is broadly similar to that predicted by MD simulations. We propose that the unique structure of the TCR β chain enables allosteric communication between the TCR binding sites for pMHC and CD3.