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Mechanism of peptide processing and loading on MHC class I molecules STEP 1: FORMATION OF THE PEPTIDE-LOADING COMPLEX The MHC class I subunits α chain and β2-microglobulin both have signal sequences that facilitate co-translational import into the endoplasmic reticulum (ER). Once in the ER, the α chain and β2-microglobulin associate with other ER-resident proteins, including calreticulin, tapasin, and ERp57, to form the peptide-loading complex.
Mechanism of peptide processing and loading on MHC class I molecules STEP 2: DIGESTION OF PROTEINS BY THE PROTEASOME Cytosolic proteins are degraded by the proteasome (a proteolytic enzyme) into smaller peptides. Inflammatory cytokines can promote the expression of a proteasome subunit to form the immunoproteasome, which facilitates MHC class I processing and presentation.
Mechanism of peptide processing and loading on MHC class I molecules STEP 3: PEPTIDE TRANSPORT INTO THE ER Peptides produced by proteasomal degradation are transported into the ER via the protein transporter associated with antigen processing (TAP).
Mechanism of peptide processing and loading on MHC class I molecules STEP 4: PEPTIDE TRIMMING Peptides that are too long to efficiently bind to the peptide-binding groove of MHC class I molecules are shortened by the endoplasmic reticulum aminopeptidase (ERAP) to the length needed (8 to 10 amino acids) for tight binding.
Mechanism of peptide processing and loading on MHC class I molecules STEP 5: TRANSPORT TO THE PLASMA MEMBRANE Loaded MHC class I molecules can then travel through the secretory pathway to the plasma membrane to present antigen to CD8 T cells.