Binding of longer peptides to the H-2Kb heterodimer is restricted to peptides extended at their C terminus: Refinement of the inherent MHC class I peptide binding criteria

Heidi Hörig, Aideen C.M. Young, Nicholas J. Papadopoulos, Teresa P. DiLorenzo, Stanley G. Nathenson

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

MHC class I molecules usually bind short peptides of 8-10 amino acids, and binding is dependent on allele-specific anchor residues. However, in a number of cellular systems, class I molecules have been found containing peptides longer than the canonical size. To understand the structural requirements for MHC binding of longer peptides, we used an in vitro class I MHC folding assay to examine peptide variants of the antigenic VSV 8 mer core peptide containing length extensions at either their N or C terminus. This approach allowed us to determine the ability of each peptide to productively form Kb2-microglobulin/peptide complexes. We found that H-2Kb molecules can accommodate extended peptides, but only if the extension occurs at the C- terminal peptide end, and that hydrophobic flanking regions are preferred. Peptides extended at their N terminus did not promote productive formation of the trimolecular complex. A structural basis for such findings comes from molecular modeling of a H-2Kb/12 mer complex and comparative analysis of MHC class I structures. These analyses revealed that structural constraints in the A pocket of the class I peptide binding groove hinder the binding of N- terminal-extended peptides, whereas structural features at the C-terminal peptide residue pocket allow C-terminal peptide extensions to reach out of the cleft. These findings broaden our understanding of the inherent peptide binding and epitope selection criteria of the MHC class I molecule. Core peptides extended at their N terminus cannot bind, but peptide extensions at the C terminus are tolerated.

Original languageEnglish (US)
Pages (from-to)4434-4441
Number of pages8
JournalJournal of Immunology
Volume163
Issue number8
StatePublished - 1999

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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