Molecular basis for specific regulation of the stress sensor IRE1 in cancer cells

The unfolded protein response (UPR) is a key adaptive cellular mechanism to detect and attenuate the accumulation of misfolded proteins inside the endoplasmic reticulum (ER). The UPR is crucial for cancer cell survival and drug resistance. This project aims to explore how IRE1 mutations associated with different cancers alter IRE1 conformation and activity. We are using biophysical and biochemistry assays and state-of-the-art structural biology approaches based on NMR, cryo-EM, and computational modeling to elucidate the molecular origins of IRE1 mutations in human cancers and understand the molecular mechanisms on how these mutations help cancer cells to survive. The project aims at invistigation of the complex IRE1 signaling mechanism as well as development of a new interdisciplinary approach for detailed characterization of multicomponent supramolecular systems.