Both α and β chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with β chain residues being most influential
| Autor: | Erik Thorsby, Tore Jensen, Ludvig M. Sollid, Frode Vartdal, Bente H. Johansen, Christopher J. Thorpe |
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| Rok vydání: | 1996 |
| Předmět: |
Models
Molecular Ovalbumin Surface Properties Genes MHC Class II Molecular Sequence Data Static Electricity Immunology Alpha (ethology) Peptide Peptide binding Biology Binding Competitive Chain (algebraic topology) HLA-DQ Antigens Genetics Humans Molecule Amino Acid Sequence Beta (finance) Cell Line Transformed chemistry.chemical_classification B-Lymphocytes Binding Sites Polymorphism Genetic Binding protein HLA-DQ2 Peptide Fragments Celiac Disease Biochemistry chemistry |
| Zdroj: | Immunogenetics. 45:142-150 |
| ISSN: | 1432-1211 0093-7711 |
| DOI: | 10.1007/s002510050182 |
| Popis: | We compared the peptide binding specificity of three HLA-DQ molecules; HLA-DQ(alpha1(*)0501, beta1(*)0201), HLA-DQ(alpha1(*)0201, beta1(*)0202), and HLA-DQ(alpha1(*)0501, beta1(*)0301). The first of these molecules confers susceptibility to celiac disease and insulin-dependent diabetes mellitus, while the two latter molecules, which share either the alpha chain or the nearly identical beta chain with HLA-DQ(alpha1(*)0501, beta1(*)0201), do not predispose to these disorders. The binding of peptides was detected in biochemical binding assays as inhibition of binding of radiolabeled indicator peptides to affinity-purified HLA-DQ molecules. Binding experiments with several peptides demonstrated a clear difference in peptide binding specificity between the three HLA-DQ molecules. Further, single amino acid substitution analyses indicated that the HLA-DQ molecules have different peptide binding motifs. The experimental data were corroborated by computer modelling analysis. Our data suggest that the three HLA-DQ molecules prefer large hydrophobic residues in P1 of peptides with subtle differences in side-chain preferences. HLA-DQ(alpha1(*)0501, beta1(*)0201) and HLA-DQ(alpha1(*)0201, beta1(*)0202) both prefer large hydrophobic residues in P9, whereas HLA-DQ(alpha1(*)0501, beta1(*)0301) prefers much smaller residues in this position. HLA-DQ(alpha1(*)0501, beta1(*)0201) and HLA-DQ(alpha1(*)0201, beta1(*)0202), in contrast to HLA-DQ(alpha1(*)0501, beta1(*)0301), prefer negatively charged residues in P4 and P7. A less prominent P6 pocket also appears to differ between the three HLA-DQ molecules. Our results indicate that polymorphic residues of both the alpha and the beta chain determine the peptide binding specificity of HLA-DQ(alpha1(*)0501, beta1(*)0201), but that the beta chain polymorphisms appears to play the most important role. The information on peptide residues which are advantageous and deleterious for binding to these HLA-DQ molecules may make possible the prediction of characteristic features of peptide that bind to HLA-DQ(alpha1(*)0501, beta1(*)0201) and precipitate celiac disease. |
| Databáze: | OpenAIRE |
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