Fig. 8. TAPBPR orthologs can enact multiple mechanisms to enable ligand exchange on MHC-I molecules.

(A) MHC-I loaded with a moderate affinity placeholder peptide can spontaneously but slowly generate empty molecules. (B) These empty molecules overcome a high-activation energy barrier (ΔG^‡uncat) to be in the transient peptide-receptive state for peptide loading. (C) A catalytic amount of TAPBPR functions to lower the activation energy barrier (ΔG^‡cat) by recognizing the empty molecules with high affinity (binding free energy ΔG_B2) and stabilizing an open conformation for peptide loading. (D) Loading of high-affinity peptides induces a closed MHC-I groove conformation leading to TAPBPR dissociation due to the substantially reduced affinity of TAPBPR toward peptide-loaded molecules (indicated by binding free energies ΔG_B1 and ΔG_B3). The reaction coordinate diagram from left to right shows the exchange of a moderate-affinity peptide to a high-affinity peptide, which can happen in the opposite direction with a much higher activation energy barrier and thus slower kinetics.