How H13 histocompatibility peptides differing by a single methyl groug and lacking conventional MHC binding anchor motifs determine self-nonself discrimination.
Animal, Asparagine, Binding-Sites, Comparative-Study, Crystallography-X-Ray, Epitope-Mapping, Epitopes, H-2-Antigens, Hybridomas, Mice, Minor-Histocompatibility-Antigens, Models-Molecular, Protein-Conformation, Receptor-CD3-Complex-Antigen-T-Cell, Self-Tolerance, SUPPORT-U-S-GOVT-NON-P-H-S, SUPPORT-U-S-GOVT-P-H-S, T-Lymphocytes-Cytotoxic, Transplantation-Tolerance, Water
J Immunol 2002 Jan; 168(1):283-289.
AI07289/AI/NIAID, AI28802/AI/NIAID, AI42970/AI/NIAID
The mouse H13 minor histocompatibility (H) Ag, originally detected as a barrier to allograft transplants, is remarkable in that rejection is a consequence of an extremely subtle interchange, P4(Val/Ile), in a nonamer H2-D(b)-bound peptide. Moreover, H13 peptides lack the canonical P5(Asn) central anchor residue normally considered important for forming a peptide/MHC complex. To understand how these noncanonical peptide pMHC complexes form physiologically active TCR ligands, crystal structures of allelic H13 pD(b) complexes and a P5(Asn) anchored pD(b) analog were solved to high resolution. The structures show that the basis of TCRs to distinguish self from nonself H13 peptides is their ability to distinguish a single solvent-exposed methyl group. In addition, the structures demonstrate that there is no need for H13 peptides to derive any stabilization from interactions within the central C pocket to generate fully functional pMHC complexes. These results provide a structural explanation for a classical non-MHC-encoded H Ag, and they call into question the requirement for contact between anchor residues and the major MHC binding pockets in vaccine design.
Ostrov, D A.; Roden, M M.; Shi, W; Palmieri, E; Christianson, G J.; Mendoza, L; Villaflor, G; Tilley, D; Shastri, N; Grey, H; Almo, S C.; Roopenian, D; and Nathenson, S G., " How H13 histocompatibility peptides differing by a single methyl groug and lacking conventional MHC binding anchor motifs determine self-nonself discrimination." (2002). Faculty Research 2000 - 2009. 340.