Modelling of the MHC II allele I-A(g7) of NOD mouse: pH-dependent changes in specificity at pockets 9 and 6 explain several of the unique properties of this molecule

Aims/hypothesis. We modelled the three-dimensional structure of I-A(g7), th e chief genetic component of diabetes in non-obese diabetic mice, to unders tand the unusual properties of this molecule. Methods. Modelling was done, in complex with established antigenic peptides , based on the structure of I-A(k). Results. The selectivity of the I-A(g7) molecule changes greatly at pockets 9 and 6 but hardly at all at pockets 1, 4 and 7, between endosomal pH (5.0 ) and extracellular pH (7.0), in agreement with previous results. This sele ctivity is attributed to the unique combination of beta 9His, beta 56His an d beta 57Ser. The positive charges in and around pocket 9 at pH 5, favour b inding by negatively charged residues. At pH 7 however, the uncharged alpha 68, beta 9 and beta 56 histidines favour the accommodation of the bulky re sidues lysine, arginine, phenylalanine and tyrosine at pocket 9. The combin ation of beta 9His and alpha 66Glu is responsible for the pH-dependent sele ctivity at pocket 6. Furthermore, the lack of repulsion between beta 56His and alpha 76Arg at pH 7 leads to a more stable ternary complex. Conclusion/interpretation. These results reconcile previous conflicts over the peptide binding ability of I-A(g7) and its motif. They furthermore prov ide possible explanations for the short lifetime of cell-surface I-A(g7) co mplexes in vivo, the higher threshold of thymic negative selection and inhe rent self-reactivity shown by immunocytes in these mice and the protection from diabetes afforded to them by several transgenically expressed mouse cl ass II alleles. This contributes to an understanding of the pathogenesis of Type I (insulin-dependent) diabetes mellitus in this animal.