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Binding of Longer Peptides to the H-2K^b Heterodimer Is Restricted to Peptides Extended at Their C Terminus: Refinement of the Inherent MHC Class I Peptide Binding Criteria ¹

Heidi Hörig^*, Aideen C. M. Young^2,*, Nicholas J. Papadopoulos^3,*, Teresa P. DiLorenzo^* and Stanley G. Nathenson^4,*,

Departments of ^* Microbiology and Immunology and Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461

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 K^b/ß₂-microglobulin/peptide complexes. We found that H-2K^b 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-2K^b/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.

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