Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into early- and late-phases

The peptide loading complex (PLC) is a multi-protein complex of the endoplasmic reticulum (ER) which optimizes major histocompatibility I (MHC1)-mediated export of intracellular high-affinity peptides. Whilst, the molecular biology of MHC1-mediated export is well supported by empirical data, the stoichiometry, kinetics and spatio-temporal profile of the participating molecular entities are a matter of considerable debate. Here, a low-affinity peptide-driven (LAPD)-model of MHC1-mediated high-affinity peptide export is formulated, implemented, analyzed and simulated. The model is parameterized in terms of the contribution of the shunt reaction to the concentration of exportable MHC1. Theoretical analyses and simulation studies of the model suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into time-dependent distinct early-and late-phases. The net exportable MHC1 (eM1 beta(t)) is a function of the retrograde (rM1 beta(t))-and anterograde (aM1 beta(t))-derived fractions. The early-phase is dominated by the contribution of the retrograde/recyclable (rM1 beta approximate to 61%, aM1 beta approximate to 39%) pathway to exportable MHC1, is characterized by Tapasin-mediated peptide-editing and is ATP- independent. The late-phase on the other hand, is characterized by de novo PLC-assembly, rapid disassembly and a significant contribution of the anterograde pathway to exportable MHC1 (rM1 beta approximate to 21%, aM1 beta approximate to 79%). The shunt reaction is rate limiting and may integrate peptide translocation with PLC-assembly/disassembly thereby, regulating peptide export under physiological and pathological (viral infections, dysplastic alterations) conditions.

Automated summary

The peptide loading complex (PLC) is a multi-protein complex of the endoplasmic reticulum (ER) that optimizes the export of high-affinity peptides mediated by major histocompatibility I (MHC1). A low-affinity peptide-driven (LAPD) model of MHC1-mediated high-affinity peptide export was formulated, implemented, analyzed, and simulated in this study. The results suggest that low-affinity peptides can bisect the export of high-affinity peptides into distinct early and late phases, with different contributions from retrograde and anterograde pathways.