Use of eluted peptide sequence data to identify the binding characteristics of peptides to the insulin-dependent diabetes susceptibility allele HLA-DQ8 (DQ 3.2) |
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Authors: | Godkin A; Friede T; Davenport M; Stevanovic S; Willis A; Jewell D; Hill A; Rammensee HG |
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Institution: | Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK. |
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Abstract: | HLA-DQ8 (A1*0301, B1*0302) and -DQ2 (A1*0501, B1*0201) are both associated
with diseases such as insulin-dependent diabetes mellitus and coeliac
disease. We used the technique of pool sequencing to look at the
requirements of peptides binding to HLA-DQ8, and combined these data with
naturally sequenced ligands and in vitro binding assays to describe a novel
motif for HLA-DQ8. The motif, which has the same basic format as many
HLA-DR molecules, consists of four or five anchor regions, in the positions
from the N-terminus of the binding core of n, n + 3, n + 5/6 and n + 8,
i.e. P1, P4, P6/7 and P9. P1 and P9 require negative or polar residues,
with mainly aliphatic residues at P4 and P6/7. The features of the HLA-DQ8
motif were then compared to a pool sequence of peptides eluted from
HLA-DQ2. A consensus motif for the binding of a common peptide which may be
involved in disease pathogenesis is described. Neither of the
disease-associated alleles HLA-DQ2 and -DQ8 have Asp at position 57 of the
beta-chain. This Asp, if present, may form a salt bridge with an Arg at
position 79 of the alpha-chain and so alter the binding specificity of P9.
HLA-DQ2 and - DQ8 both appear to prefer negatively charged amino acids at
P9. In contrast, HLA-DQ7 (A1*0301, B1*0301), which is not associated with
diabetes, has Asp at beta 57, allowing positively charged amino acids at
P9. This analysis of the sequence features of DQ-binding peptides suggests
molecular characteristics which may be useful to predict epitopes involved
in disease pathogenesis.
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