Disordered by design

During periods of protein folding stress, the transmembrane protein IRE1 detects misfolded proteins in the endoplasmic reticulum (ER) and initiates a transcriptional relay as part of the unfolded protein response (UPR). In order to signal the presence of unfolded proteins in the ER, IRE1 oligomerizes, but the molecular mechanisms behind this process remain unknown. In a recent study from the Karagöz lab published in EMBO Journal, first authors Paulina Kettel, PhD student, and Laura Marosits, then research associate, provide the first evidence that disordered regions in IRE1’s ER luminal sensor domain regulate its self-assembly. Their discoveries could help pave the way for the development of drugs that target diseases associated with protein misfolding.