Both alpha and beta chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with beta chain residues being most influential

Immunogenetics. 1996;45(2):142-50. doi: 10.1007/s002510050182.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • B-Lymphocytes / metabolism
  • Binding Sites
  • Binding, Competitive
  • Celiac Disease / genetics
  • Celiac Disease / immunology*
  • Cell Line, Transformed
  • Genes, MHC Class II*
  • HLA-DQ Antigens / genetics*
  • HLA-DQ Antigens / metabolism
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Ovalbumin / immunology
  • Ovalbumin / metabolism
  • Peptide Fragments / metabolism
  • Polymorphism, Genetic*
  • Static Electricity
  • Surface Properties


  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • Peptide Fragments
  • Ovalbumin