Please use this identifier to cite or link to this item: doi:10.22028/D291-30505
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Title: Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca2+ Leakage from the Endoplasmic Reticulum
Author(s): Gamayun, Igor
O'Keefe, Sarah
Pick, Tillman
Klein, Marie-Christine
Nguyen, Duy
McKibbin, Craig
Piacenti, Michela
Williams, Helen M.
Flitsch, Sabine L.
Whitehead, Roger C.
Swanton, Eileithyia
Helms, Volkhard
High, Stephen
Zimmermann, Richard
Cavalié, Adolfo
Language: English
Title: Cell chemical biology
Volume: 26
Issue: 4
Startpage: 571
Endpage: 583
Publisher/Platform: Elsevier
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:
Link to this record: hdl:20.500.11880/28885
ISSN: 2451-9456
Date of registration: 20-Mar-2020
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Biowissenschaften
Professorship: NT - Prof. Dr. Volkhard Helms
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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