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Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation

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. and Shi, Wei Q. (2019) Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation Journal of the American Chemical Society, 141 (21). pp. 8450-8461.

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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 Sec61α (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 Sec61α 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. Sec61α 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 Sec61α provides compelling evidence that Sec61α is the primary molecular target of ipomoeassin F and strongly suggests that the binding of this natural product to Sec61α is distinctive. Therefore, ipomoeassin F represents the first plant-derived, carbohydrate-based member of a novel structural class that offers new opportunities to explore Sec61α function and to further investigate its potential as a therapeutic target for drug discovery.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Zong, Guanghui
Hu, Zhijian
O’Keefe, Sarah
Tranter, Dale
Iannotti, Michael J.
Baron, Ludivine
Corfield, Katherine
Paatero, Anja O.
Henderson, Mark J.
Roboti, Peristera
Zhou, Jianhong
Sun, Xianwei
Govindarajan, Mugunthan
Rohde, Jason M.
Blanchard, Nicolas
Inglese, James
Du, Yuchun
Demangel, Caroline
High, Stephen
Paavilainen, Ville O.
Shi, Wei Q.
Date : 29 May 2019
Funders : Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust
DOI : 10.1021/jacs.8b13506
Copyright Disclaimer : © 2019 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Depositing User : Clive Harris
Date Deposited : 05 Sep 2019 07:32
Last Modified : 05 Sep 2019 07:32

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