MHC class I molecules can direct proteolytic cleavage of antigenic precursors in the endoplasmic reticulum

The large set of peptides presented by MHC (major histocompatibility comple x) class I molecules are generated by proteolysis of diverse precursors in the cytoplasm and possibly in the endoplasmic reticulum (ER). To define the potential peptide trimming events in the ER, we analyzed proteolytic produ cts generated in isolated microsomes. The residues flanking the N terminus of the final antigenic peptide were rapidly removed within the microsomes b ut only in the presence of appropriate MHC molecules. Remarkably, the precu rsor peptide was bound to the MHC molecules in a distinct conformation and required an aminopeptidase activity to generate the optimal peptide. The MH C molecules are therefore not only the final repositories of antigenic pept ides, but they can also direct their excision from longer precursors.