Figure 3.

Proposed model of tapasin (Tsn)-catalyzed peptide proofreading. According to the model of Tsn-catalyzed peptide proofreading, Tsn scans the quality of major histocompatibility complex class I (MHC I)-bound peptides with regard to their affinity by sensing and acting on the α_2-1 helix, a structural element close to the C-terminal anchor region of the peptide (F pocket). Intrinsic flexibility of the α_2-1 helix is depicted by cartoon-blur semicircles. Peptide dissociation in the absence of Tsn can result in partial unfolding of the MHC molecule. Upon being confronted with a suboptimally loaded MHC I molecule (step 1), Tsn presumably stabilizes an open conformation of the binding groove by interacting with the α_2-1 helix, inducing peptide dissociation and stabilizing the resulting empty MHC (step 2). Only high-affinity peptides can subsequently compete with Tsn over the α_2-1 helix to tighten the binding groove again (step 3). This lowers the Tsn–MHC affinity and eventually triggers Tsn dissociation (step 4). As a result, the peptide repertoire presented on MHC I at the cell surface is enriched with high-affinity peptide epitopes capable of triggering an immune response (step 5). The quintessence of the MHC I peptide-proofreading mechanism might be considered as a tug-of-war between Tsn and the peptide over the α_2-1 helix and the opening/closing of the binding groove.