POLYMORPHISM IN THE ALPHA(1) HELIX OF THE HLA-B HEAVY-CHAIN CAN HAVE AN OVERRIDING INFLUENCE ON PEPTIDE-BINDING SPECIFICITY

Previously, we reported overlap in the repertoires of peptides endogen ously bound by a group of HLA-B allotypes related to HLA-B7. Extending such analysis to four members of the B17 family and seven members of the B15 family shows that allotypes that share sequence identity in th e alpha(1) helix of the class I heavy chain possess markedly similar p eptide-binding specificities. Members of the B17 family share a prefer ence for peptides with serine, threonine, or alanine at position 2 and aromatic residues at the carboxyl terminus. Strikingly, the presence of a segment of the B17 alpha(1) helix in B1516 and B*1517 confers th e B17-like peptide-binding motif. The strong influence of natural vari ation in the alpha(1) helix is exemplified by the differences in pepti de-binding specificity of B15 allotypes related by conversion events t hat replaced segments of the alpha(1) helix. In contrast, evolutionary changes that are confined to the alpha(2) domain confer less dramatic change. They do not perturb the primary anchors of the peptide-bindin g motif but can modulate the specificity through development and diver sification of secondary anchors. Our results, in combination with thos e obtained previously for other HLA-B allotypes, suggest a general tre nd whereby polymorphism in the alpha(1) helix is the overriding influe nce on peptide-binding specificity of HLA-B allotypes, while amino aci d substitutions in the alpha(2) domain play a more modulatory role.