The structure of the antigen-binding groove of major histocompatibility complex class I molecules determines specific selection of self-peptides.
We have examined the effect of diversity in the antigen-binding groove of the Kb, Db, Kbm1, and Kbm8 major histocompatibility complex (MHC) class I molecules on the set of self-peptides they present on the cell surface, by using a procedure we recently developed in our laboratory to isolate endogenously processed peptides bound to MHC class I molecules. We found that such naturally processed peptides are 7-10 amino acids long. A major motif of tyrosine and phenylalanine residues at positions three and five was found for peptides binding to Kb. The availability of Kb mutant molecules Kbm1 and Kbm8, each with localized clustered changes in the antigen-binding cleft, allowed us to probe the effect of such small alterations on peptide selection. We found that such changes in different regions in the antigen-binding groove exert an absolute effect by changing subsets of self-peptides bound to these MHC molecules. In the Kbm1 mutant, the binding of the characteristic major set of Kb-associated peptides with tyrosine at position three or both positions three and five is abrogated, although this MHC molecule still binds peptides with tyrosine at position seven; the latter peptides also bind to Kb. Kbm8 shares the major Tyr-3, Tyr-5 peptide set that binds to Kb but does not bind the peptides with tyrosine at position seven. Thus differences in binding selectivity in Kbm1 and Kbm8 appear to be the major determinant for the observed alterations in in vivo immune responses.
van Bleek
G M
GM
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461.
Nathenson
S G
SG
D000595:Amino Acid Sequence; D000818:Animals; D000936:Antigen-Antibody Complex / Q000032:analysis*; D001665:Binding Sites; D001666:Binding Sites, Antibody; D002460:Cell Line; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010446:Peptide Fragments / Q000302:isolation & purification; D011487:Protein Conformation
D000936:Antigen-Antibody Complex; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments