Abstract
We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells. Recognition by these sentinels of the immune system can lead to the destruction of the presenting cell, thus protecting the host from pathogens and cancer. Classical MHC class I molecules (MHC I hereafter) are co-dominantly expressed, polygenic, and exceptionally polymorphic and have significant sequence diversity. Thus, in most species, there are many different MHC I allotypes expressed, each with different peptide-binding specificity, which can have a dramatic effect on disease outcome. Although MHC allotypes vary in their primary sequence, they share common tertiary and quaternary structures. Here, we review the evidence that, despite this commonality, polymorphic amino acid differences between allotypes alter the ability of MHC I molecules to change shape (that is, their conformational plasticity). We discuss how the peptide loading co-factor tapasin might modify this plasticity to augment peptide loading. Lastly, we consider recent findings concerning the functions of the non-classical MHC I molecule HLA-E as well as the tapasin-related protein TAPBPR (transporter associated with antigen presentation binding protein-related), which has been shown to act as a second quality-control stage in MHC I antigen presentation.
Highlights
We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells
Concluding remarks There is a huge array of potential peptide epitopes that could bind to MHC I molecules and be presented to the immune system, but only a small fraction are bound by MHC I molecules and presented
Perhaps the biggest recent advance concerning MHC I antigen presentation is that we have greater appreciation that MHC I molecules, in the empty state, are dynamic proteins that bend, flex, twist, and crunch with consummate ease
Summary
Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions. The functional relevance of this membrane-proximal interaction is supported by two further findings: firstly, that mutagenesis of a natural polymorphism in the α3 domain of chicken MHC I allotypes, that is predicted to participate in this interaction, influences the ability of tapasin to enhance peptide dissociation[63]; secondly, that mimicking the membrane-proximal interaction between the α3 domain and tapasin increases the exploration of different peptide-binding domain conformations[39] Taken together, these observations are consistent with a model where tapasin binding to MHC I via two distinct sites modulates the plasticity of the bound MHC I molecule in such a way as to shift the equilibrium towards peptide-receptive MHC I conformations (Figure 2B).
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