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 p eptide binding properties and intracellular behavior of I-A(g7) in com parison with other I-A haplotypes, We found that I-A(g7) molecules man ifested normal intracellular trafficking and lifespan, and a small but clearly detectable fraction of I-A(g7) in the cells formed SDS-resist ant compact dimers, The binding of an antigenic reference peptide to I -A(g7) was stable and was accompanied by compact dimer formation, Our analysis of the binding specificity of I-A(g7) revealed a peptide bind ing motif of nine amino acids with a degenerate position at P1 and thr ee conserved anchor positions: P4, P6 and P9, An allele-specific prefe rence 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) beta chain, These findings could have implications for the mechanisms of MHC-mediated susceptibility to autoimmune diabetes in the NOD mice.