Structure of a Classical MHC Class I Molecule That Binds “Non-Classical” Ligands

Abstract

Chicken YF1 genes share a close sequence relationship with classical MHC class I loci but map outside of the core MHC region. To obtain insights into their function, we determined the structure of the YF1*7.1/β₂-microgloblin complex by X-ray crystallography at 1.3 Å resolution. It exhibits the architecture typical of classical MHC class I molecules but possesses a hydrophobic binding groove that contains a non-peptidic ligand. This finding prompted us to reconstitute YF1*7.1 also with various self-lipids. Seven additional YF1*7.1 structures were solved, but only polyethyleneglycol molecules could be modeled into the electron density within the binding groove. However, an assessment of YF1*7.1 by native isoelectric focusing indicated that the molecules were also able to bind nonself-lipids. The ability of YF1*7.1 to interact with hydrophobic ligands is unprecedented among classical MHC class I proteins and might aid the chicken immune system to recognize a diverse ligand repertoire with a minimal number of MHC class I molecules. Proteins encoded by the major histocompatibility complex (MHC) play crucial roles in vertebrate immune systems, presenting pathogen-derived protein fragments to receptors on effector cells. In contrast, some non-classical MHC class I proteins such as CD1 molecules possess a hydrophobic groove that allows them to display lipids. Chicken MHC-Y is a genetic region outside the core MHC that harbors several immune-related genes, among them YF1*7.1, which encodes a protein whose structure we solved in this study. YF1*7.1 is an MHC class I molecule that exhibits the architecture typical of classical MHC class I antigens but possesses a hydrophobic binding groove that binds non-peptidic ligands. By using lipid-binding assays, we show that this molecule can indeed bind lipids. Therefore, YF1*7.1 bridges, at least in structural terms, the traditional gap between classical and non-classical MHC class I molecules. Lipid-binding YF1 proteins might serve the chicken to enlarge its otherwise very small repertoire of antigen-presenting MHC class I molecules. Furthermore, comparative analyses of the two protein subunits of classical MHC molecules revealed a structural feature in chickens that appears to be shared by non-mammalian but not by mammalian vertebrates. This unique feature is indicative of a structure-dependent co-evolution of two genetically unlinked genes in non-mammalian species.