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Dr. Peter Cresswell

Eugene Higgins Professor of Immunobiology
Investigator, Howard Hughes Medical Institute
Yale University School of Medicine

Ìý

Antigenic peptides generated in the cytosol are translocated into the endoplasmic reticulum by the ATP-dependent ‘Transporter associated with Antigen Processing’ (TAP), where they bind to newly synthesized MHC class I molecules. TAP, together with the MHC class I molecule itself, and calreticulin, ERp57 and the specialized glycoprotein, tapasin, form the peptide loading complex (PLC).Ìý Tapasin is critical for loading MHC class I molecules with high affinity peptides. It functions within the PLC as a disulfide-linked, stable heterodimer with the thiol oxidoreductase ERp57, and this covalent interaction is required to support optimal PLC activity. The structure of the tapasin/ERp57 dimer revealed the basis for the stable dimerization of tapasin and ERp57 and provided the first example of a protein disulfide isomerase family member interacting with a substrate. Mutational analysis has mapped a conserved surface on tapasin that interacts with MHC class I molecules and is critical for the peptide loading function of the tapasin-ERp57 heterodimer. These results illuminate the processes involved in MHC class I peptide loading.