The P9 pocket of HLA-DQ2 (non-Aspbeta57) has no particular preference for negatively charged anchor residues found in other type 1 diabetes- predisposing non-Aspbeta57 MHC class II molecules

• DOI: 10.1093/intimm/10.8.1229
• Publication Date: 2002-07-26T22:47:51Z
• Authors: H Quarsten
• Keywords: Salt bridge; Residue (chemistry)

Susceptibility and resistance to type 1 diabetes are associated with MHC class II alleles that carry non-Asp Asp at residue 57 of their beta chain respectively. The effect or non-Aspbeta57 may relate a differential ability distinct molecules bind specific immuno-pathogenic peptides. Recent studies in man mouse have revealed some diabetes-predisposing (i.e. DQ8, DR4Dw15 I-Ag7) preferentially peptides negatively charged anchor P9. It has been suggested this is common feature molecules. molecular explanation for such phenomenon could be chains Aspbeta57 form salt bridge between conserved Arg the chain, whereas unopposed free interact P9 peptide residues. We investigated specificity pocket diabetes-associated DQ2 molecule particular examined charge effects position. Different approaches were undertaken. analyzed binding high-affinity ligand P9-substituted variants peptide, we set synthetic random libraries. analyses performed wild-type mutated Ala beta57 substituted Asp. Our results indicate (non-Aspbeta57) prefers large hydrophobic residues there no preference DQ altered, indicating contributes determining pocket. data do not lend support hypothesis all predispose development disease by