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Polymorphism at Position 97 in MHC Class I Molecules Affects Peptide Specificity, Cell Surface Stability, and Affinity for ₂-Microglobulin¹

Ruth A. Smith^2,*, Nancy B. Myers, Melanie Robinson^*, Ted H. Hansen and David R. Lee^3,*

^* Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212; and Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110

The two mouse MHC class I alleles, L^d and L^q, share complete amino acid sequence identity except in the 2 domain, where they differ at six positions. Despite their similarity, L^q has a stronger association with ₂-microglobulin (₂m), is expressed at higher levels on the cell surface, demonstrates an increased cell surface half-life, and has fewer open forms on the cell surface than L^d. To determine the basis for their phenotypic differences, L^d molecules containing chimeric L^d-L^q 2 domains were characterized, and these analyses implicated residue 97 (L^dTrp and L^qArg) as the polymorphic site responsible for the disparity in ₂m association between the two alleles. Single substitution analysis at this site (L^dW97R and L^qR97W) confirmed this. Furthermore, the L^dW97R mutant molecule has a longer cell surface half-life than either L^q or L^d, and fewer open forms of L^dW97R are observed on the cell surface. In addition, both L^dW97R and L^q possess decreased binding affinity for the L^d-restricted tum^- P91A_14–22 peptide compared with L^d. Collectively, these results and the known location of Trp⁹⁷ in the peptide binding cleft of L^d strongly suggest that the substitution of Arg for Trp⁹⁷ in L^d alters the peptide binding cleft, increasing its affinity for endogenous peptides, which results in greater cell surface stability and better retention of ₂m. Furthermore, these results imply that Trp⁹⁷ plays an important role in the ability of L^d to efficiently participate in alternative MHC class I Ag presentation pathways.

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