The endoplasmic reticulum supports the biogenesis and maturation of approximately one-third of the human proteome, including most secreted proteins and many membrane proteins. The accumulation of improperly folded proteins can activate the stress sensor IRE1a, initiating adaptive stress response (UPR). Dysregulation of this response is implicated in several diseases, including cancer and metabolic disorders. IRE1a also responds to changes in membrane lipids, but the underlying molecular mechanisms remain poorly understood. This PhD project aims to understand how the membrane environment influences IRE1a structure and dynamics. It will focus on its membrane-spanning region and the flexible linker connecting it to the signaling domains. The work will involve producing protein fragments and studying them in membranes with controlled lipid compositions. Solution and solid-state nuclear magnetic resonance (NMR) spectroscopy will provide atomic-level information about these regions. Complementary biochemical and biophysical approaches will characterize their self-association and interactions with lipids. The aim is to identify how lipids affect the organization of the membrane-spanning region and the mobility of the flexible linker. Studying fragments containing both regions will help test how these effects are transmitted between them. The results will provide a structural basis for understanding IRE1a regulation and its role in stress responses.