The endoplasmic reticulum is the largest membrane system in most eukaryotic cells. It is where ~30% of the proteome folds, where calcium is stored at 104-fold over cytosolic concentrations, where phospholipids and cholesterol are synthesised, and where chronic stress tips the cell toward programmed death. Our new 7-module ER course covers the organelle from Palade’s first EM images to the clinical UPR modulators in trial for neurodegeneration.
Seven Modules
- M0 — Architecture & Discovery: Palade, sheets vs tubules vs three-way junctions, reticulons and atlastin, SPG3A/SPG4 as ER-shape diseases.
- M1 — Cotranslational Translocation: Blobel signal hypothesis (1999 Nobel), SRP/SR cycle, Sec61 translocon, lateral gate, positive-inside rule, GET/TRC40 and EMC post-translational insertases.
- M2 — Folding & Chaperones: BiP/Hsp70 ATP cycle, calnexin/UGGT iterative proof-reading, oxidative folding via PDI/Ero1, GRP94 specialised substrates.
- M3 — ERAD & Quality Control: Hrd1/Sel1L retrotranslocation, p97/Cdc48 AAA+ ATPase, substrate categories L/M/C, ER-phagy (FAM134B).
- M4 — Unfolded Protein Response: IRE1 & XBP1s, PERK & eIF2α/ATF4/CHOP, ATF6 Golgi cleavage. ODE simulation of the bifurcation from adaptive to apoptotic. ISRIB and PERK inhibitors.
- M5 — Lipids, Ca²⁺ & Contact Sites: ER as lipid factory, SREBP sterol sensing, SERCA/IP3R/RyR, STIM-Orai SOCE, MAMs, non-vesicular lipid transfer at contact sites.
- M6 — ER in Disease: CF & Trikafta correctors, α1-antitrypsin polymerisation and fazirsiran, neurodegeneration and chronic UPR, β-cell ER stress in diabetes, multiple myeloma’s UPR addiction.
Python Simulations
Every module includes executable simulations: bending cost of ER tubules, S/V ratios, Kyte-Doolittle hydropathy and topology prediction, iterative folding cycles, folding vs degradation kinetic race, UPR ODE dynamics across stress levels, ER Ca2+ dynamics with IP3R release and SOCE refill. Run them in the browser and modify parameters.