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|Title:||Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca2+ Leakage from the Endoplasmic Reticulum|
Williams, Helen M.
Flitsch, Sabine L.
Whitehead, Roger C.
|Title:||Cell chemical biology|
|Year of Publication:||2019|
|Publikation type:||Journal Article|
|Abstract:||Eeyarestatin 1 (ES1) inhibits p97-dependent protein degradation, Sec61-dependent protein translocation into the endoplasmic reticulum (ER), and vesicular transport within the endomembrane system. Here, we show that ES1 impairs Ca2+ homeostasis by enhancing the Ca2+ leakage from mammalian ER. A comparison of various ES1 analogs suggested that the 5-nitrofuran (5-NF) ring of ES1 is crucial for this effect. Accordingly, the analog ES24, which conserves the 5-NF domain of ES1, selectively inhibited protein translocation into the ER, displayed the highest potency on ER Ca2+ leakage of ES1 analogs studied and induced Ca2+-dependent cell death. Using small interfering RNA-mediated knockdown of Sec61α, we identified Sec61 complexes as the targets that mediate the gain of Ca2+ leakage induced by ES1 and ES24. By interacting with the lateral gate of Sec61α, ES1 and ES24 likely capture Sec61 complexes in a Ca2+-permeable, open state, in which Sec61 complexes allow Ca2+ leakage but are translocation incompetent.|
|DOI of the first publication:||10.1016/j.chembiol.2019.01.010|
|URL of the first publication:||https://www.sciencedirect.com/science/article/pii/S2451945619300327|
|Link to this record:||hdl:20.500.11880/28885|
|Date of registration:||20-Mar-2020|
|Faculty:||NT - Naturwissenschaftlich- Technische Fakultät|
|Department:||NT - Biowissenschaften|
|Professorship:||NT - Prof. Dr. Volkhard Helms|
|Collections:||UniBib – Die Universitätsbibliographie|
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