Fig. 7. Proposed model of auxiliary peptide editing functions of TAPBPR.

a Schematic of how the TAPBPR G24-R36 loop influences the peptide exchange cycle. The G24-R36 loop serves as a trap, promoting peptide binding on the MHC-I/TAPBPR complex with low μM affinity. When TAPBPR is mutated to have a shorter loop, the affinity of peptides is reduced to high μM range. b Conceptual example of the free energy landscape across the cellular peptide pool. The TAPBPR G24-R36 loop shapes the selected peptide repertoire by stabilizing peptide binding across the cellular pool, functioning as an auxiliary loading chaperone for peptides of low and moderate affinity. c In the ER, peptide selection is governed both by the effective concentration of peptides and the absence (in tapasin) or the presence of the kinetic trap (in TAPBPR). Tapasin is tethered to the TAP transporter and because it is restricted to an environment of high peptide concentration and has a shorter loop, it primarily loads high-affinity peptides. In contrast, TAPBPR is not tethered to TAP and because it functions in environments of lower peptide concentration, it employs a trap to load both high and moderate affinity peptides and/or to minimize dissociation of peptides during transient TAPBPR/pMHC-I interactions. This process results in a diverse peptide repertoire being displayed by MHC-I molecules on the cell surface.