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Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-Susceptible HLA-DQB1*06 Alleles¹

Ruth A. Ettinger^2,*,, George K. Papadopoulos, Antonis K. Moustakas, Gerald T. Nepom^*, and William W. Kwok^*,

^* Benaroya Research Institute at Virginia Mason, Seattle, WA 98101 and Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece; and Department of Biological Agriculture, Technological Educational Institute of Ionian Islands, Argostoli, Cephallonia, Greece

HLA-DQA1*0102-DQB1*0602 is associated with protection against type 1 diabetes (T1D). A similar allele, HLA-DQA1*0102-DQB1*0604, contributes to T1D susceptibility in certain populations but differs only at seven amino acids from HLA-DQA1*0102-DQB1*0602. Five of these polymorphisms are found within the peptide-binding groove, suggesting that differences in peptide binding contribute to the mechanism of their association with T1D. In this study, we determine the peptide-binding motif for HLA-DQA1*0102-DQB1*0604 allelic protein (DQ0604) in comparison to the established HLA-DQA1*0102-DQB1*0602 (DQ0602) motif using binding assays with model peptides from T1D autoantigens and homology modeling using the coordinates of the DQ0602-hypocretin 1–13 crystal structure. The peptide binding preferences were deduced with a peptide from insulin that bound both with a 2- to 3-fold difference in avidity using the same amino acids in the peptide as anchors. Peptide binding differences directly influenced by the polymorphisms in or nearby pockets 1, 6, and 9 were observed. In pocket 1, DQ0604 was better able to accommodate aromatic residues due to the 86 and 87 polymorphisms. A negatively charged amino acid was preferred by DQ0604 in pocket 6 due to the positively charged 30His. In pocket 9, DQ0604 preferred aromatic amino acids due to the 9 and 30 polymorphisms and had low tolerance of acidic residues. 57Val in DQ0604 functions differently than 57Ala, in that it pushes 76Arg outside of the pocket, preventing the formation of a salt bridge with an acidic amino acid in the peptide. This study furthers our understanding of the structure-function relationships of MHC class II polymorphisms.

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The JI 2006 177: 1373-1374. [Full Text]  

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