The unfolded protein response (UPR) is triggered when misfolded secretory and membrane proteins accumulate within the endoplasmic reticulum (ER). It remains unclear how the misfolded state of proteins in the ER is sensed by the transmembrane signal transducing kinase, Ire1. Gardner and Walter (see the Perspective by Kawaguchi and Ng) now provide evidence that supports the notion that Ire1 directly interacts with misfolded proteins, thereby leading to dimerization and activation of Ire1. Yeast in vitro experiments showed that the luminal domain of Ire1 can bind to peptides enriched in hydrophobic and basic residues typical of misfolded proteins. Furthermore, a misfolded model protein directly interacted with Ire1 in intact yeast cells.
- Directing Quality Control
A newly synthesized secretory protein quality control pathway is activated by direct binding of misfolded proteins to a sensor in the endoplasmic reticulum.Permalink: