A Glycopeptide in Complex with MHC Class I Uses the GalNAc Residue as an Anchor

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-12, Vol.100 (25), p.15029-15034
• Main Authors: Apostolopoulos, Vasso, Yuriev, Elizabeth, Ramsland, Paul A., Halton, Jodie, Osinski, Carla, Li, Wenjun, Plebanski, Magdalena, Paulsen, Hans, Ian F. C. Mc Kenzie
• Format: Article
• Language: English
• Subjects: Acetylgalactosamine - chemistry; Amino acids; Animals; Antigens; Binding Sites; Biological Sciences; Crystal structure; Cultured cells; Enzyme-Linked Immunosorbent Assay; Female; Genes, MHC Class I; Glycopeptides; Glycopeptides - chemistry; Hydrogen Bonding; Hydrogen bonds; Immunology; Interferon-gamma - metabolism; Mice; Mice, Inbred C57BL; Models, Molecular; Molecular interactions; Molecules; Peptides; Peptides - chemistry; Protein Binding; Protein Structure, Secondary; T cell antigen receptors; T lymphocytes; T lymphoid precursor cells; Temperature; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2432220100

Peptides bind MHC class I molecules by anchoring hydrophobic side chains into pockets in the peptide binding groove. Here, we report an immunogenic (in vitro and in vivo) MUC1 glycopeptide (MUC1-8-5GalNAc) bound to H-2Kb, fully crossreactive with the nonglycosylated variant. Molecular modeling showed that the central P5-Thr-GalNAc residue points into the C pocket and forms van der Waals and hydrogen bond interactions with the MHC class I. As predicted, GalNAc, a modified peptide carrying an additional anchor in the central C anchor pocket, increased the affinity by ≈100-fold compared with the native low-affinity peptide (MUC1-8). The findings demonstrate that glycopeptides associated with MHC class I molecules can use GalNAc to anchor the peptide in the groove and enable high-affinity binding.