Abstract
The adaptive immune system is able to detect and destroy cells that are malignantly transformed or infected by intracellular pathogens. Specific immune responses against these cells are elicited by antigenic peptides that are presented on major histocompatibility complex class I (MHC I) molecules and recognized by cytotoxic T lymphocytes at the cell surface. Since these MHC I-presented peptides are generated in the cytosol by proteasomal protein degradation, they can be metaphorically described as a window providing immune cells with insights into the state of the cellular proteome. A crucial element of MHC I antigen presentation is the peptide-loading complex (PLC), a multisubunit machinery, which contains as key constituents the transporter associated with antigen processing (TAP) and the MHC I-specific chaperone tapasin (Tsn). While TAP recognizes and shuttles the cytosolic antigenic peptides into the endoplasmic reticulum (ER), Tsn samples peptides in the ER for their ability to form stable complexes with MHC I, a process called peptide proofreading or peptide editing. Through its selection of peptides that improve MHC I stability, Tsn contributes to the hierarchy of immunodominant peptide epitopes. Despite the fact that it concerns a key event in adaptive immunity, insights into the catalytic mechanism of peptide proofreading carried out by Tsn have only lately been gained via biochemical, biophysical, and structural studies. Furthermore, a Tsn homolog called TAP-binding protein-related (TAPBPR) has only recently been demonstrated to function as a second MHC I-specific chaperone and peptide proofreader. Although TAPBPR is PLC-independent and has a distinct allomorph specificity, it is likely to share a common catalytic mechanism with Tsn. This review focuses on the current knowledge of the multivalent protein–protein interactions and the concomitant dynamic molecular processes underlying peptide-proofreading catalysis. We do not only derive a model that highlights the common mechanistic principles shared by the MHC I editors Tsn and TAPBPR, and the MHC II editor HLA-DM, but also illustrate the distinct quality control strategies employed by these chaperones to sample epitopes. Unraveling the mechanistic underpinnings of catalyzed peptide proofreading will be crucial for a thorough understanding of many aspects of immune recognition, from infection control and tumor immunity to autoimmune diseases and transplant rejection.
Highlights
molecules is fundamental to the recognition
Peptides derived from intracellular pathogens
transporter associated with antigen processing
Summary
Presentation of antigenic peptides on major histocompatibility complex class I (MHC I) molecules is fundamental to the recognition of infected and cancerous cells by the immune system [1]. Wearsch and Cresswell used soluble, recombinantly generated Tsn–ERp57 conjugate and cell extracts of Tsn-negative cells transfected with HLA-B8 to provide evidence that Tsn–ERp57 promotes the exchange of intermediate- and low-affinity peptides for high-affinity epitopes [12] These initial demonstrations of Tsn-catalyzed peptide dissociation and discrimination of unstable peptide–MHC I complexes have later been confirmed by analyzing peptide loading onto the mouse MHC I allele H2-Kb using isolated microsomes [30]. To further biochemically dissect the Tsn–MHC I interaction and the peptide-editing process in vitro, a tethering approach was employed that incorporated ERp57 and used recombinant biotinylated Tsn and MHC together with dimeric neutravidin to mimic the structural organization of Tsn–ERp57 and MHC I within the PLC By combining this strategy with photo-cleavable peptide to synchronize and follow the catalytic process in real time, it was possible to demonstrate that Tsn increases the dissociation rate of low- and intermediate-affinity (suboptimal) peptide epitopes up to 10-fold [40].
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