TCR-MHC docking orientation: natural selection, or thymic selection?

Abstract

T cell receptors (TCR) dock on their peptide-major histocompatibility complex (pMHC) targets in a conserved orientation. Since amino acid sidechains are the foundation of specific protein-protein interactions, a simple explanation for the conserved docking orientation is that key amino acids encoded by the TCR and MHC genes have been selected and maintained through evolution in order to preserve TCR/pMHC binding. Expectations that follow from the hypothesis that TCR and MHC evolved to interact are discussed in light of the data that both support and refute them. Finally, an alternative and equally simple explanation for the driving force behind the conserved docking orientation is described.