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Peptide Selection by an MHC H-2K^b Class I Molecule Devoid of the Central Anchor ("C") Pocket¹

Alberto Molano, Hediye Erdjument-Bromage^*, Daved H. Fremont^§, Ilhem Messaoudi, Paul Tempst^*, and Janko Nikoli-ugi^2,

Immunology and ^* Molecular Biology Programs, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; Sloan-Kettering Division, Cornell University Graduate School of Medical Sciences, New York, NY 10021; Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, Columbia University, New York, NY 10168; and ^§ National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206

The peptide-binding site of the murine MHC class I molecule H-2K^b contains a deep C pocket, that is critical for peptide binding, as it accepts the anchor phenylalanine or tyrosine residue located in the middle (position 5, P5F/Y) of H-2K^b binding peptides. H-2K^b predominantly binds octameric peptides. By both criteria, H-2K^b is unique among the known murine and human class I molecules, none of which have a deep C pocket or preferentially select octamers. We investigated the relative importance of the C pocket in peptide selection and binding by the MHC. An MHC class I H-2K^b variant, K^bW9, predicted to contain no C pocket, was engineered by replacing valine at MHC9 with tryptophan. This mutation drastically altered the selection of peptides bound to K^bW9. The K^bW9 molecule predominantly, if not exclusively, bound nonamers. New peptide anchor residues substituted for the loss of the P5F/Y:C pocket interaction. P3P/Y, which plays an auxiliary role in binding to K^b, assumed the role of a primary anchor, and P5R was selected as a new primary anchor, most likely contacting the E pocket. These experiments demonstrate that the presence of a deep C pocket is responsible for the selection of octameric peptides as the preferred ligands for K^b and provide insight into the adaptation of peptides to a rearranged MHC groove.

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