The MHC class II molecule I-A(g7) exists in alternate conformations that are peptide dependent

Insulin-dependent diabetes mellitus is an autoimmune disease that is geneti cally linked to the HLA class II molecule DQ in humans and to MHC I-A(g7) i n nonobese diabetic mice. The I-A(g7) beta-chain is unique and contains mul tiple polymorphisms, at least one of which is shared with DQ alleles linked to insulin-dependent diabetes mellitus. This polymorphism occurs at positi on 57 in the beta-chain, in which aspartic acid is mutated to a serine, a c hange that results in the loss of an interchain salt bridge between alpha A rg(76) and beta Asp(57) at the periphery of the peptide binding groove. Usi ng mAbs we have identified alternative conformations of I-A(g7) class II mo lecules. By using an invariant chain construct with various peptides engine ered into the class II-associated invariant chain peptide (CLIP) region we have found that formation of these conformations is dependent on the peptid e occupying the binding groove. Blocking studies with these Abs indicate th at these conformations are present at the cell surface and are capable of i nteractions with TCRs that result in T cell activation.