Modelling of the MHC II allele I-A(g7) of NOD mouse: pH-dependent changes in specificity at pockets 9 and 6 explain several of the unique properties of this molecule
| Autor: | John Routsias, George K. Papadopoulos, Antonis K. Moustakas |
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| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular Chemical Phenomena Endocrinology Diabetes and Metabolism Molecular Sequence Data Peptide binding Biology Negative selection Mice Structure-Activity Relationship Mice Inbred NOD Internal Medicine Electrochemistry Structure–activity relationship Animals Amino Acid Sequence Binding site Tyrosine Ternary complex Peptide sequence NOD mice Binding Sites Chemistry Physical Histocompatibility Antigens Class II Hydrogen-Ion Concentration Diabetes Mellitus Type 1 Biochemistry Crystallization Sequence Alignment |
| Zdroj: | Diabetologia. 43(5) |
| ISSN: | 0012-186X |
| Popis: | Aims/hypothesis We modelled the three-dimensional structure of I-A(g7), 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-A(k). Results The selectivity of the I-A(g7) 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 beta9His, beta56His and beta57Ser. The positive charges in and around pocket 9 at pH 5, favour binding by negatively charged residues. At pH 7 however, the uncharged alpha68, beta9 and beta56 histidines favour the accommodation of the bulky residues lysine, arginine, phenylalanine and tyrosine at pocket 9. The combination of beta9His and alpha66Glu is responsible for the pH-dependent selectivity at pocket 6. Furthermore, the lack of repulsion between beta56His and alpha76Arg at pH 7 leads to a more stable ternary complex. Conclusion/interpretation These results reconcile previous conflicts over the peptide binding ability of I-A(g7) and its motif. They furthermore provide possible explanations for the short lifetime of cell-surface I-A(g7) 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. |
| Databáze: | OpenAIRE |
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