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Eeyarestatin Compounds Selectively Enhance Sec61-Mediated Ca2+ Leakage from the Endoplasmic Reticulum.
- Source :
-
Cell Chemical Biology . Apr2019, Vol. 26 Issue 4, p571-571. 1p. - Publication Year :
- 2019
-
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. • ES1, ES2, and ES24 deplete Ca2+ in ER • ESR35 and ES47 do not affect cellular Ca2+ homeostasis • The most potent eeyarestatin, ES24, comprises only the 5-nitrofuran domain • ES1 and ES24 target Sec61 complexes in ER Gamayun et al. discovered that eeyarestatins (ESs) interfere with closing mechanisms of Sec61 complexes of the ER and, as a "foot in the door," stabilize Sec61 complexes in a Ca2+-permeable, open state. Specifically, ES24 enhances strongly the Sec61-mediated Ca2+ leakage from ER and induces Ca2+-dependent cell death. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 24519456
- Volume :
- 26
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Cell Chemical Biology
- Publication Type :
- Academic Journal
- Accession number :
- 136350342
- Full Text :
- https://doi.org/10.1016/j.chembiol.2019.01.010