Abstract
Knowledge about the magnitude of individual polymorphism is a critical part in understanding the complexity of comprehensive mismatching. HLA-B*44:09 differs from the highly frequent HLA-B*44:02 allele by amino acid exchanges at residues 77, 80, 81, 82 and 83. We aimed to identify the magnitude of these mismatches on the features of HLA-B*44:09 bound peptides since residues 77, 80 and 81 comprise part of the F pocket which determines sequence specificity at the pΩ position of the peptide. Using soluble HLA technology we determined >200 individual (nonduplicate) self-peptides from HLA-B*44:09 and compared their features with that of the published peptide features of HLA-B*44:02. Both alleles illustrate an anchor motif of E at p2. In contrast to the C-terminal peptide binding motif of B*44:02 (W, F, Y or L), B*44:09-derived peptides are restricted predominantly to L or F. The source of peptides for both alleles is identical (LCL 721.221 cells) allowing us to identify 23 shared peptides. The majority of these peptides however contained the restricted B*44:09 anchor motif of F or L at the pΩ position. Molecular modelling based on the B*44:02 structure highlights that the differences of the C-terminal peptide anchor between both alleles can be explained primarily by the B*44:0281Ala > B*44:0981Leu polymorphism which restricts the size of the amino acid that can be accommodated in the F pocket of B*44:09. These results highlight that every amino acid substitution has an impact of certain magnitude on the alleles function and demonstrate how surrounding residues orchestrate peptide specificity.
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Acknowledgments
The technical assistance of Susanne Aufderbeck is gratefully acknowledged. This work was supported by a grant from the German Federal Ministry of Education and Research (reference number 01E00802).
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Huyton, T., Schumacher, H., Blasczyk, R. et al. Residue 81 confers a restricted C-terminal peptide binding motif in HLA-B*44:09. Immunogenetics 64, 663–668 (2012). https://doi.org/10.1007/s00251-012-0625-1
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DOI: https://doi.org/10.1007/s00251-012-0625-1