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CUTTING EDGE |
*
Department of Chemistry, University of Washington, Seattle, WA 98195; and
Department of Pathology and Committees on Immunology and Cancer Biology, University of Chicago, Chicago, IL 60637
The binding of peptides to MHC class II molecules is mediated in part by a conserved array of intermolecular hydrogen bonds. We have evaluated the consequences of disrupting the hydrogen bond between ß-His-81 of the class II molecule and bound peptide. These studies revealed that peptide dissociation rates were accelerated by factors ranging to 200-fold. The sensitivity of a peptide to loss of the hydrogen bond is inversely correlated with the inherent kinetic stability of the peptide-MHC complex. The same relationship has been observed between inherent kinetic stability and the susceptibility to DM. Given that the rate enhancement observed for MHC class II I-Ad protein mutated at position 81 in the ß-chain is comparable with DM-catalyzed rates for other class II molecules, we suggest that DM could function by stabilizing a peptide-MHC intermediate in which one or more hydrogen bonds between the peptide and MHC, such as that contributed by the ß-His-81 hydrogen bond, are disrupted.
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