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bioRxiv · 10.1101/2023.05.26.542528

Bilayer tension-induced clustering of the UPR sensor IRE1

Hossain, M. Z.·Stroberg, W.
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Abstract

The endoplasmic reticulum acts as a protein quality control center where a range of chaperones and foldases facilitates protein folding. IRE1 is a sensory trans-membrane protein that transduces signals of proteotoxic stress by forming clusters and activating a cellular program called the unfolded protein response (UPR). Recently, membrane thickness variation due to membrane compositional changes have been shown to drive IRE1 cluster formation, activating the UPR even in the absence of proteotoxic stress. Here, we demonstrate a direct relationship between bilayer tension and UPR activation based on IRE1 dimer stability. The stability of the IRE1 dimer in a (50%DOPC-50%POPC) membrane at different applied bilayer tensions was analyzed via molecular dynamics simulations. The potential of mean force for IRE1 dimerization predicts a higher concentration of IRE1 dimers for both tensed and compressed ER membranes. This study shows that IRE1 may be a mechanosensitive membrane protein and establishes a direct biophysical relationship between bilayer tension and UPR activation. HighlightsO_LIMechanical perturbation of the ER membrane favor oligomerization. C_LIO_LIBoth tension and compression promote IRE1 dimer formation. C_LIO_LIIRE1 is mechanosensitive, potentially the UPR to changes in ER membrane tension and compression. C_LI

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Hossain, M. Z., Stroberg, W.. 2023-05-26. Bilayer tension-induced clustering of the UPR sensor IRE1. https://doi.org/10.1101/2023.05.26.542528

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