Mathematical modelling of mutant glycoprotein fate in the ER
Created March 19, 2026
Updated on March 25, 2026
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Mathematical modelling of mutant glycoprotein fate in the ER
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10.64898/2025.11.30.691435
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publication
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Daniele Di Bella, orcid: 0009-0009-9581-4317 ; Andrea Lia, orcid: 0000-0003-4146-0647 ; Pietro Roversi, orcid: 0000-0001-9280-9437
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<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p> The endoplasmic reticulum (ER) coordinates glycoprotein quality control through competing pathways: ER quality control (ERQC) and ER-associated degradation (ERAD). The fate of a glycoprotein is tied to its <jats:italic>N</jats:italic> -glycan(s) structure, which serves as a “molecular barcode” for quality control. In particular, modulation of ERQC/ERAD can increase leakage of responsive ( <jats:italic>i.e</jats:italic> ., non-inactive) glycoprotein mutants that remain misfolded yet retain biological activity once outside the ER. Rescue of secretion of such mutants is a promising therapeutic strategy for the therapy of congenital rare disease due to a missense mutation in a secreted glycoprotein gene, but the relative merits of UGGT <jats:italic>vs</jats:italic> . EDEM inhibition to release a mutant from the ER remain to be explored. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> An ordinary differential equation (ODE) framework (“ER Glycoprotein Outcome”, ERGO) evaluates time-dependent ER concentrations of 13 <jats:italic>N</jats:italic> -glycospecies of a single mutant glycoprotein (G1M9, G1M8B, G1M8C, G1M7BC, M9, M8A, M8B, M8C, M7AB, M7AC, M7BC, M6, M5) within the ER lumen, under a set of chosen hypotheses. All reactions follow mass-action kinetics with ER enzymes/lectins kinetic constants and concentrations as fixed parameters. The ODE system is solved in <jats:monospace>Python</jats:monospace> with adaptive Runge-Kutta integration. Simulations initialise from a single glycofo
Publication Date
2025-12-02
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openRxiv
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false
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false
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Last Updated
March 25, 2026, 10:38 (UTC)
Created
March 19, 2026, 00:15 (UTC)
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