BACKGROUND

T cells form one of the key pillars of adaptive immunity. Using their surface bound T cell antigen receptors (TCRs), these cells screen millions of antigens presented by major histocompatibility complex (MHC) or MHC-like molecules. In other protein families, the dynamics of protein-protein interactions have important implications for protein function. Case studies of TCR:class I peptide-MHCs (pMHC-Is) structures have reported mixed results on whether the binding interfaces undergo conformational change during engagement and no robust statistical quantification has been done to generalise these results. Thus, it remains an open question of whether movement occurs in the binding interface that enables the recognition and activation of T cells.

METHODS

In this work, we quantify the conformational changes in the TCR:pMHC-I binding interface by creating a dataset of 391 structures, comprising 22 TCRs, 19 MHC alleles, and 79 peptide structures in both unbound (apo) and bound (holo) conformations.

RESULTS

In support of some case studies, we demonstrate that all complementarity determining region (CDR) loops move to a certain extent but only CDR3α and CDR3β loops modify their shape when binding pMHC-Is. We also map the contacts between TCRs and pMHC-Is, generating a novel fingerprint of TCRs on MHC molecules and show that the CDR3α tends to bind the N-terminus of the peptide and the CDR3β tends to bind the C-terminus of the peptide. Finally, we show that the presented peptides can undergo conformational changes when engaged by TCRs, as has been reported in past literature, but novelly show these changes depend on how the peptides are anchored in the MHC binding groove.

CONCLUSIONS

Our work has implications in understanding the behaviour of TCR:pMHC-I interactions and providing insights that can be used for modelling Tcell antigen specificity, an ongoing grand challenge in immunology.