Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.03.30.534746v1?rss=1

Authors: Kettel, P., Marosits, L., Spinetti, E., Rechberger, M., Radler, P., Niedermoser, I., Fischer, I., Versteeg, G. A., Loose, M., Covino, R., Karagoz, G. E.

Abstract:
Upon accumulation of unfolded proteins at the endoplasmic reticulum (ER), IRE1 activates the unfolded protein response (UPR) to restore protein-folding homeostasis. During ER stress, the ER lumenal domain (LD) of IRE1 drives its clustering on the ER membrane to initiate signaling. How IRE1 LD assembles into high-order oligomers remains largely unknown. By in vitro reconstitution experiments we show that human IRE1 LD forms dynamic biomolecular condensates. IRE1 LD condensates were stabilized when IRE1 LD was tethered to model membranes and upon binding of unfolded polypeptide ligands. Molecular dynamics simulations suggested that weak multivalent interactions are involved in IRE1 LD assemblies. Mutagenesis showed that disordered regions in IRE1 LD control its clustering in vitro and in cells. Importantly, dysregulated clustering led to defects in IRE1 signaling. Our results reveal that membranes and unfolded polypeptides act as scaffolds to assemble dynamic IRE1 condensates into stable, signaling competent clusters.

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