We examine the effect of mutations in the HLA-B*0702 α1 domain on the binding of several well-characterized monoclonal antibodies. BB7.1 recognizes the α-helix, with a special requirement for residue 67. Combined with an established requirement for the α2 α-helix, BB7.1 appears to span the B*0702 peptide-binding groove. Alternatively, BB7.1 epitope conformation may be altered by distant B*0702 sites. ME1 and B27M1 recognize connecting loop residues 41 and 43 and α1 α-helical residues 67-71. Instead of contacting residue 67-71 side chains directly, however, ME1 appears to recognizes a B*0702 configuration that depends upon the proper interaction of these and other HLA residues. In addition to solvent-accessible residues 41 and 43, the B27M1 epitope depends on solvent-inaccessible residue 32 at the bottom of the peptide-binding groove. MB40.2, known to require residues 169-182 near the α2-α3 junction, also requires the proper combination of distant residues in the α1 β-strand and α-helix. The effect of mutations near the peptide-binding groove suggests that bound peptides may directly or indirectly affect HLA epitopes. These results illustrate that HLA epitope conformation is very sensitive to changes at distant HLA sites and forecast that epitope models based on sequential amino acid residues will often fail to predict HLA epitopes.
ASJC Scopus subject areas
- Immunology and Allergy