Allele-specific motifs characterize HLA-DQ interactions with a diabetes-associated peptide derived from glutamic acid decarboxylase.

Polymorphic residues of HLA class II molecules influence immune activation in part by determining specific structural constraints for binding antigenic peptides. We identified a peptide from glutamic acid decarboxylase, a diabetes-associated autoantigen that preferentially bound to HLA-DQ3.2 molecules, one of the HLA determinants highly associated with insulin-dependent diabetes. We analyzed interactions of specific HLA-DQ residues with modified peptide analogues and found a pattern of permissive site-specific amino acids that accommodated allele-specific binding. Four anchor residues constrain binding to different DQ alleles; limited variation at two of these sites, residues 4 and 9, accounts for the unique pattern of peptide binding to HLA-DQ3.1 or HLA-DQ3.2.