Ipomoeassin F Binds Sec61 alpha to Inhibit Protein Translocation

Show full item record



Permalink

http://hdl.handle.net/10138/304273

Citation

Zong , G , Hu , Z , O'Keefe , S , Tranter , D , Iannotti , M J , Baron , L , Hall , B , Corfield , K , Paatero , A O , Henderson , M J , Roboti , P , Zhou , J , Sun , X , Govindarajan , M , Rohde , J M , Blanchard , N , Simmonds , R , Inglese , J , Du , Y , Demangel , C , High , S , Paavilainen , V O & Shi , W Q 2019 , ' Ipomoeassin F Binds Sec61 alpha to Inhibit Protein Translocation ' , Journal of the American Chemical Society , vol. 141 , no. 21 , pp. 8450-8461 . https://doi.org/10.1021/jacs.8b13506

Title: Ipomoeassin F Binds Sec61 alpha to Inhibit Protein Translocation
Author: Zong, Guanghui; Hu, Zhijian; O'Keefe, Sarah; Tranter, Dale; Iannotti, Michael J.; Baron, Ludivine; Hall, Belinda; Corfield, Katherine; Paatero, Anja O.; Henderson, Mark J.; Roboti, Peristera; Zhou, Jianhong; Sun, Xianwei; Govindarajan, Mugunthan; Rohde, Jason M.; Blanchard, Nicolas; Simmonds, Rachel; Inglese, James; Du, Yuchun; Demangel, Caroline; High, Stephen; Paavilainen, Ville O.; Shi, Wei Q.
Contributor: University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
University of Helsinki, Institute of Biotechnology
Date: 2019-05-29
Language: eng
Number of pages: 12
Belongs to series: Journal of the American Chemical Society
ISSN: 0002-7863
URI: http://hdl.handle.net/10138/304273
Abstract: Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61 alpha (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells. The interaction is specific and strong enough to survive lysis conditions, enabling a biotin analogue of ipomoeassin F to pull down Sec61 alpha from live cells, yet it is also reversible, as judged by several experiments including fluorescent streptavidin staining, delayed competition in affinity pulldown, and inhibition of TNF biogenesis after washout. Sec61 alpha forms the central subunit of the ER protein translocation complex, and the binding of ipomoeassin F results in a substantial, yet selective, inhibition of protein translocation in vitro and a broad ranging inhibition of protein secretion in live cells. Lastly, the unique resistance profile demonstrated by specific amino acid single-point mutations in Sec61 alpha provides compelling evidence that Sec61 alpha is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61 alpha is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61 alpha function and to further investigate its potential as a therapeutic target for drug discovery.
Subject: NATURAL-PRODUCTS
BIOLOGICAL EVALUATION
RESIN GLYCOSIDES
MYCOLACTONE
INSIGHTS
APRATOXIN
BLOCKADE
SQUAMOSA
REVEALS
ANALOGS
1182 Biochemistry, cell and molecular biology
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
jacs.8b13506.pdf 4.412Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record