Molecular characterization of the diabetes-associated mouse MHC class II protein, I-A(g7)

The MHC class II molecule of the non-obese diabetic (NOD) mice, I-A(g7), is associated with susceptibility to autoimmune diabetes. To try to understand the molecular basis of this association, we analyzed the peptide binding properties and intracellular behavior of I-A(g7) in comparison with other I-A haplotypes. We found that I-A(g7) molecules manifested normal intracellular trafficking and lifespan, and a small but clearly detectable fraction of I-A(g7) in the cells formed SDS-resistant compact dimers. The binding of an antigenic reference peptide to 1-A(g7) was stable and was accompanied by compact dimer formation. Our analysis of the binding specificity of I-A(g7) revealed a peptide binding motif of nine amino acids with a degenerate position at pi and three conserved anchor positions: P4, P6 and P9. An allele-specific preference for negatively charged residues was found at P9, apparently due to the presence of the rare Ser residue at position 57 of the I-A(g7) β chain. These findings could have implications for the mechanisms of MHC-mediated susceptibility to autoimmune diabetes in the NOD mice.