RECOGNITION OF A SINGLE AMINO-ACID CHANGE ON THE SURFACE OF A MAJOR TRANSPLANTATION ANTIGEN IS IN THE CONTEXT OF SELF-PEPTIDE

The transcripts encoding two strongly alloantigenic class I mutant mol ecules, K-dm4 and K-dm5, were characterized and found to encode produc ts that differ from the parental K-d glycoprotein by single amino acid substitutions. The K-dm4 molecule has an amino acid change at positio n 114, an integral component of a beta-sheet associated with pockets D and E of the peptide binding site. The basis for strong alloantigenic ity of the variant molecule can be attributed to differences in peptid e binding that were visualized by HPLC analysis of eluted peptides. In contrast, the K-dm5 molecule differs from the parent at position 158, a component of the alpha-helix that is not associated with any of the pockets of the peptide binding site. No differences in peptide bindin g by K-dm5 in comparison with the parent K-d molecule were seen by HPL C, suggesting that the variant and parent molecules bind the same set of peptides. The ability of (dm4 X dm5) F1 hybrid mice to recognize an d lyse BALB/c stimulator cells indicates that the alloantigenic proper ties determined by the 158 substitution result from the interactions o f the alpha-helix regions (changed in dm5) with the pockets of the bin ding site (changed in dm4). We conclude that self peptides shared by t he F1 hybrid and the BALB/c stimulator cells are recognized in the con text of structural features of the helices of the Ag-presenting molecu le as alloantigenic determinants.