caa a22 4500 475772830 CHVBK 20180406123622.0 cr unu---uuuuu 170329e20000501xx s 000 0 eng 10.1007/s001250051350 doi (NATIONALLICENCE)springer-10.1007/s001250051350 Modelling of the MHC II allele I-Ag7 of NOD mouse: pH-dependent changes in specificity at pockets 9 and 6 explain several of the unique properties of this molecule [Elektronische Daten] [A. K. Moustakas, J. Routsias, G. K. Papadopoulos] Abstract : Aims/hypothesis. We modelled the three-dimensional structure of I-Ag7, the chief genetic component of diabetes in non-obese diabetic mice, to understand the unusual properties of this molecule. Methods. Modelling was done, in complex with established antigenic peptides, based on the structure of I-Ak. Results. The selectivity of the I-Ag7 molecule changes greatly at pockets 9 and 6 but hardly at all at pockets 1, 4 and 7, between endosomal pH (5.0) and extracellular pH (7.0), in agreement with previous results. This selectivity is attributed to the unique combination of β9His, β56His and β57Ser. The positive charges in and around pocket 9 at pH 5, favour binding by negatively charged residues. At pH 7 however, the uncharged α68, β9 and β56 histidines favour the accommodation of the bulky residues lysine, arginine, phenylalanine and tyrosine at pocket 9. The combination of β9His and α66Glu is responsible for the pH-dependent selectivity at pocket 6. Furthermore, the lack of repulsion between β56His and α76Arg at pH 7 leads to a more stable ternary complex. Conclusion/interpretation. These results reconcile previous conflicts over the peptide binding ability of I-Ag7 and its motif. They furthermore provide possible explanations for the short lifetime of cell-surface I-Ag7 complexes in vivo, the higher threshold of thymic negative selection and inherent self-reactivity shown by immunocytes in these mice and the protection from diabetes afforded to them by several transgenically expressed mouse class II alleles. This contributes to an understanding of the pathogenesis of Type I (insulin-dependent) diabetes mellitus in this animal. [Diabetologia (2000) 43: 609-624] Springer-Verlag Berlin Heidelberg, 2000 Keywords Autoimmunity nationallicence I-Ag7 molecule nationallicence MHC class II structure nationallicence protein modelling nationallicence NOD mice nationallicence Type I diabetes mellitus nationallicence Moustakas A. K. Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece, GR aut Routsias J. Laboratory of Immunology, Department of Internal Medicine, University of Ioannina Medical School, Ioannina, Greece, GR aut Papadopoulos G. K. Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece, GR aut https://doi.org/10.1007/s001250051350 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s001250051350 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Moustakas A. K. Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece, GR aut NATIONALLICENCE 700 1- Routsias J. Laboratory of Immunology, Department of Internal Medicine, University of Ioannina Medical School, Ioannina, Greece, GR aut NATIONALLICENCE 700 1- Papadopoulos G. K. Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece, GR aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer