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 sto...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844021015693 |
| _version_ | 1819137592762826752 |
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| author | Siddhartha Kundu |
| author_facet | Siddhartha Kundu |
| author_sort | Siddhartha Kundu |
| collection | DOAJ |
| description | 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 (eM1β(t)) is a function of the retrograde (rM1β(t))- and anterograde (aM1β(t))-derived fractions. The “early”-phase is dominated by the contribution of the retrograde/recyclable (rM1β≈61%,aM1β≈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 (rM1β≈21%,aM1β≈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. |
| first_indexed | 2024-12-22T10:53:20Z |
| format | Article |
| id | doaj.art-bf586303850b49928d833ca99c79717a |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-12-22T10:53:20Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-bf586303850b49928d833ca99c79717a2022-12-21T18:28:41ZengElsevierHeliyon2405-84402021-07-0177e07466Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phasesSiddhartha Kundu0Corresponding author.; Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi – 110029, IndiaThe 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 (eM1β(t)) is a function of the retrograde (rM1β(t))- and anterograde (aM1β(t))-derived fractions. The “early”-phase is dominated by the contribution of the retrograde/recyclable (rM1β≈61%,aM1β≈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 (rM1β≈21%,aM1β≈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.http://www.sciencedirect.com/science/article/pii/S2405844021015693Low-affinity peptidesMajor histocompatibility complexPeptide loading complexPLC-assembly/disassemblyPeptide editingShunt reaction |
| spellingShingle | Siddhartha Kundu Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phases Heliyon Low-affinity peptides Major histocompatibility complex Peptide loading complex PLC-assembly/disassembly Peptide editing Shunt reaction |
| title | Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phases |
| title_full | Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phases |
| title_fullStr | Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phases |
| title_full_unstemmed | Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phases |
| title_short | Mathematical modeling and stochastic simulations suggest that low-affinity peptides can bisect MHC1-mediated export of high-affinity peptides into “early”- and “late”-phases |
| title_sort | mathematical modeling and stochastic simulations suggest that low affinity peptides can bisect mhc1 mediated export of high affinity peptides into early and late phases |
| topic | Low-affinity peptides Major histocompatibility complex Peptide loading complex PLC-assembly/disassembly Peptide editing Shunt reaction |
| url | http://www.sciencedirect.com/science/article/pii/S2405844021015693 |
| work_keys_str_mv | AT siddharthakundu mathematicalmodelingandstochasticsimulationssuggestthatlowaffinitypeptidescanbisectmhc1mediatedexportofhighaffinitypeptidesintoearlyandlatephases |