title: Peptide selection by an MHC H-2Kb class I molecule devoid of the central anchor ("C") pocket.
abstract: The peptide-binding site of the murine MHC class I molecule H-2Kb 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-2Kb binding peptides. H-2Kb predominantly binds octameric peptides. By both criteria, H-2Kb 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-2Kb variant, Kbw9, 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 Kbw9. The Kbw9 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 Kb, 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 Kb and provide insight into the adaptation of peptides to a rearranged MHC groove.
authors.affiliation: Sloan-Kettering Division, Cornell University Graduate School of Medical Sciences, New York, NY 10021, USA.
authors.forename: A
authors.initials: A
authors.lastname: Molano
authors.forename: H
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: D H
authors.initials: DH
authors.lastname: Fremont
authors.forename: I
authors.initials: I
authors.lastname: Messaoudi
authors.forename: P
authors.initials: P
authors.lastname: Tempst
authors.forename: J
authors.initials: J
authors.lastname: Nikolić-Zugić
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006183:H-2 Antigens / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry*; D015202:Protein Engineering; D013329:Structure-Activity Relationship
chemical_list: D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D010455:Peptides