Structural diversity of class I MHC-like molecules and its implications in binding specificities

The binding groove of class I major histocompatibility complex (MHC) class is essentially important for antigen binding and presentation on T cells. There are several molecules that have analogous conformations to class I MHC. However, they bind specifically to varying types of ligands and cell-surface receptors in order to elicit an immune response. To elucidate how such recognition is achieved in classical MHC-I like molecules, we have extensively analyzed the structure of human leukocyte antigen (HLA-1), neonatal Fc receptor (FcRn), hereditary hemochromatosis protein (HFE), cluster of differentiation 1 (CD1), gamma delta T cell receptor ligand (Τ22), zinc-α2-glycoprotein (ZAG), and MHC class I chain-related (MIC-A) proteins. All these molecules have analogous structural anatomy, divided into three distinct domains, where α1-α2 superdomains form a groove-like structure that potentially bind to certain ligand, while the α3 domain adopts a fold resembling immunoglobulin constant domains, and holds this α1-α2 platform and the light chain. We have observed many remarkable features of α1-α2 platform, which provide specificities to these proteins toward a particular class of ligands. The relative orientation of α1, α2, and α3 domains is primarily responsible for the specificity to the light chain. Interestingly, light chain of all these proteins is β₂-microglobulin (β₂M), except ZAG which has prolactin-induced protein (PIP). However, MIC-A is devoid of any light chain. Residues on β₂M recognize a sequence motif on the α3 domain that is essentially restricted to specific heavy chain of MHC class I molecules. Our analysis suggests that the structural features of class I molecules determine the recognition of different ligands and light chains, which are responsible for their corresponding functions through an inherent mechanism.