title: Ovalbumin(323-339) peptide binds to the major histocompatibility complex class II I-A(d) protein using two functionally distinct registers.
abstract: Proteins of the class II major histocompatibility complex (MHC) bind antigenic peptides that are subsequently presented to T cells. Previous studies have shown that most of the residues required for binding of the chicken ovalbumin (Ova) 323-339 peptide to the I-A(d) MHC class II protein are contained within the shorter 325-336 peptide. This observation is somewhat inconsistent with the X-ray structure of the Ova peptide covalently attached to I-A(d) ( structure) in which residues 323 and 324 form binding interactions with the protein. A second register for the Ova(325-336) peptide is proposed where residues 326 and 327 occupy positions similar to residues 323 and 324 in the structure. Two Ova peptides that minimally encompass the and alternate registers, Ova(323-335) and Ova(325-336), respectively, were found to dissociate from I-A(d) with distinct kinetics. The dissociation rates for both peptides were enhanced when the His81 residue of the MHC beta-chain was replaced with an asparagine. In the structure the betaH81 residue forms a hydrogen bond to the backbone carbonyl of I323. If the Ova(325-336) peptide were also bound in the register, there would be no comparable hydrogen-bond acceptor for the betaH81 side chain that could explain this peptide's sensitivity to the betaH81 replacement. The Ova(323-335) peptide that binds in the register does not stimulate a T-cell hybridoma that is stimulated by Ova(325-336) bound in the alternate register. These results demonstrate that a single peptide can bind to an MHC peptide in alternate registers producing distinct T-cell responses.
authors.affiliation: Department of Chemistry, University of Washington, Seattle 98195, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: McFarland
authors.forename: A J
authors.initials: AJ
authors.lastname: Sant
authors.forename: T P
authors.initials: TP
authors.lastname: Lybrand
authors.forename: C
authors.initials: C
authors.lastname: Beeson
mesh_terms: D000818:Animals; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D010047:Ovalbumin / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D016056:Immunodominant Epitopes; C111390:OVA 323-339; D010446:Peptide Fragments; D010047:Ovalbumin