MHC I chaperone complexes shaping immunity

Major histocompatibility complex class I (MHC I) molecules present peptides on the surface of most nucleated cells and allow the immune system to detect and eliminate infected or malignantly transformed cells. The peptides are derived from endogenous proteins by proteasomal degradation or aberrant translation, and are translocated from the cytosol into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), a central component of the peptide-loading complex (PLC). The peptides are subsequently processed by ER-resident aminopeptidases (ERAP1/2) and loaded onto MHC I. This loading, however, does not happen indiscriminately: in a process called peptide editing or peptide proofreading, the MHC I-specific chaperones tapasin and TAPBPR (TAP-binding protein-related) catalyze the selection of high-affinity peptides and stable peptide-MHC I (pMHC I) complexes. Once correctly loaded with a high-affinity peptide, pMHC I complexes travel to the cell surface where they are recognized by T lymphocytes to control their differentiation in the thymus, their priming in the lymph node, and their final long-term surveillance of target cells in the periphery. Recent structural studies of the PLC and of TAPBPR-MHC I complexes by single-particle cryo-electron microscopy, X-ray crystallography, and NMR spectroscopy have provided fundamental insights into the mechanisms of MHC I peptide loading and proofreading, highlighting the dynamic nature of the involved complexes and the conformational plasticity of the individual proteins.