MHC-TCR Docking orientation

Structural studies have been made of many (>25) TCR-pMHC complexes, of both MHC classes, and many similarities have been found.

Typically, the TCR docks on pMHC in a central diagonal orientation, with the variable α domain over the N-terminal half of the antigenic peptide and the variable β domain over the C-terminal half, though the exact conformation may vary. This pattern is also present in the molecule studied here (see images; different angles used to show proximity). Like in other known MHC-TCR interactions, it is the CDR3 of the two variable domains that interacts mostly with the peptide fragment.

The question arises: Why? Why this specific orientation, and why is it this highly conserved? Two hypotheses have been proposed to explain this (which are not mutually exclusive). The first is that co-evolution of MHC and TCR has given  rise to specific interactions between the α helices in TCR and the CDR1-2 domains, restricting the geometry of the structure. This is suggested partly by certain highly conserved amino acids present in the relevant α helices of MHC. These amino acids are located in cups inside the not entirely straight helices, and are thus particularly restrictive. This applies to both MHC I and MHC II (see figure).

Position of highly conserved amino acids in MHC alpha-helices

The second proposed hypothesis states that it is not evolution that causes this geometric restriction, but T-cell development. During positive selection of T-cells, co-receptor stimulation is required in order for the T-cells to survive, and any T-cells that have a different topology will not be capable of binding an MHC molecule with both TCR and CD4 and will thus die off.

Having a complete structure of the ternary complex also allows conslusions to be drawn regarding the plausibility of these hypotheses. The relative positions of the CD4 and TCR anchor points allow the authors to predict the positions of intra-cellular proteins and to conclude that, if the docking polarity were reversed (i.e. variable α domain interacting with C-terminus of peptide), then the CD4 associated Lck would be impeded from phosphorylating the CD3 ITAMs, blocking downstream signalling from occuring.