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 [Formula: see text] is a function of the retrograde ([Formula: see text])- and anterograde ([Formula: see text])-derived fractions. The “early”-phase is dominated by the contribution of the retrograde/recyclable ([Formula: see text]) 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 ([Formula: see text]). 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.