The kinetic basis of peptide exchange catalysis by HLA-DM

The mechanism by which the peptide exchange factor HLA-DM catalyzes peptide loading onto structurally homologous class II MHC proteins is an outstandi ng problem in antigen presentation. The peptide-loading reaction of class I I MHC proteins is complex and includes conformational changes in both empty and peptide-bound forms in addition to a bimolecular binding step. By usin g a fluorescence energy transfer assay to follow the kinetics of peptide bi nding to the human class II MHC protein HLA-DR1, we find that HLA-DM cataly zes peptide exchange by facilitating a conformational change in the peptide -bound complex, and not by promoting the bimolecular MHC-peptide reaction o r the conversion between peptide-receptive and -averse forms of the empty p rotein. Thus, HLA-DM serves essentially as a protein-folding or conformatio nal catalyst.