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A healthy proteome is critical for every organism. Cells constantly need to monitor their proteins and respond to physiological and pathological conditions that perturb the delicate balance between protein synthesis, folding and degradation. In the endoplasmic reticulum (ER), the protein-folding homeostasis is surveyed by a conserved signaling network called the unfolded protein response (UPR). The main purpose of the UPR is to adjust the ER’s folding capacity. How sensors and transducers detect protein-folding problems and mount an appropriate response is a major open question.
In my lab, we seek to understand the UPR at a mechanistic level. We combine cell biology and biochemistry to dissect how cells maintain a protein-folding homeostasis in the ER. Using next generation sequencing and proteomic approaches, we obtain global information on the molecular components regulating ER-quality control. We then reconstitute these processes biochemically and apply structural methods to dissect their working principles at atomic resolution. Our long-term goal is to use the mechanistic insights derived from these approaches to restore protein homeostasis in variety human diseases caused by protein misfolding.
Elif Karagöz majored Molecular Biology and Genetics with a minor in Chemistry at the Middle East Technical University in Turkey. She got her Master’s degree in Molecular Biology at the Max Planck Research School in Göttingen. After completing her PhD at Utrecht University in the group of Stefan Rüdiger, she did a postdoc at Peter Walter’s lab at the University of California San Francisco.
The UPR sensors directly detect unfolded proteins accumulating in the ER as activating ligands. ER-chaperones also bind the UPR sensors and regulate their activation/deactivation dynamics. In my lab, we dissect how the interplay among unfolded proteins, sensors and chaperones tunes the UPR using biochemical, structural, and cell biology approaches.
Protein synthesis and folding is tightly coupled to allow error-free assembly of the proteome. Posttranscriptional regulation provides rapid and reversible means for tuning protein synthesis, yet the mechanisms regulating the fate of ER-targeted mRNAs during protein folding stress remain largely unknown. To this end, we aim to reveal how translation and stability of ER-targeted mRNAs are regulated to maintain ER homeostasis.
The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1.
Acosta-Alvear, Diego; Karagöz, Gülsün Elif; Fröhlich, Florian; Li, Han; Walther, Tobias C; Walter, Peter
An unfolded protein-induced conformational switch activates mammalian IRE1.
Karagöz, G Elif; Acosta-Alvear, Diego; Nguyen, Hieu T; Lee, Crystal P; Chu, Feixia; Walter, Peter
Hsp90-Tau complex reveals molecular basis for specificity in chaperone action.
Karagöz, G Elif; Duarte, Afonso M S; Akoury, Elias; Ippel, Hans; Biernat, Jacek; Morán Luengo, Tania; Radli, Martina; Didenko, Tatiana; Nordhues, Bryce A; Veprintsev, Dmitry B; Dickey, Chad A; Mandelkow, Eckhard; Zweckstetter, Markus; Boelens, Rolf; Madl, Tobias; Rüdiger, Stefan G D