The I-A(g7) MHC class II molecule linked to murine diabetes is a promiscuous peptide binder

Susceptibility to insulin-dependent diabetes mellitus is linked to MHC clas s II genes. The only MHC class II molecule expressed by nonobese diabetic ( NOD) mice, I-A(g7), shares a common alpha -chain with I-Ad brat has a pecul iar beta -chain, As with most beta -chain alleles linked to diabetes suscep tibility, I-A(g7) contains a nonaspartic residue at position beta 57, We ha ve produced large amounts of empty I-A(g7) molecules using a fly expression system to characterize its biochemical properties and peptide binding by p hage-displayed peptide libraries. The identification of a specific binding peptide derived from glutamic acid decarboxylase (GAD65) has allowed us to crystallize and obtain the three-dimensional structure of I-A(g7). Structur al information was critical in evaluating the binding studies. I-A(g7), lik e I-A(d), appears to be very promiscuous in terms of peptide binding. Their binding motifs are degenerate and contain small and/or small hydrophobic r esidues at P4 and P6 of the peptide, a motif frequently found in most globu lar proteins, The degree of promiscuity is increased for I-Ap7 over I-A(d) as a consequence of a larger P9 pocket that can specifically accommodate ne gatively charged residues, as well as possibly residues with bulky side cha ins. So, although I-Ad and I-A(g7) are structurally closely related, stable molecules and good peptide binders, they differ functionally in their abil ity to bind significantly different peptide repertoires that are heavily in fluenced by the presence or the absence of a negatively charged residue at position 57 of the beta -chain, These characteristics link I-A(g7) with aut oimmune diseases, such as insulin-dependent diabetes mellitus.