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

Abstract

Aims/hypothesis. We modelled the three-dimensional structure of I-A(g7), the chief genetic component of diabetes in non-obese diabetic mice, to understand the unusual properties of this molecule. Methods. Modelling was done, in complex with established antigenic peptides, based on the structure of IA(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 selectivity is attributed to the unique combination of β9His, β56His and β57Ser. The positive charges in and around pocket 9 at pH 5, favour binding by negatively charged residues. At pH 7 however, the uncharged α68, β9 and β56 histidines favour the accommodation of the bulky residues lysine, arginine, phenylalanine and tyrosine at pocket 9. The combination of β9His and α66Glu is responsible for the pH-dependent selectivity at pocket 6. Furthermore, the lack of repulsion between β56His and α76Arg 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 provide possible explanations for the short lifetime of cell-surface I-A(g7) complexes in vivo, the higher threshold of thymic negative selection and inherent self-reactivity shown by immunocytes in these mice and the protection from diabetes afforded to them by several transgenically expressed mouse class II alleles. This contributes to an understanding of the pathogenesis of Type I (insulin-dependent) diabetes mellitus in this animal.