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Article Dans Une Revue Journal of the American Chemical Society Année : 2019

Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation

Sarah O’keefe
  • Fonction : Auteur
Dale Tranter
  • Fonction : Auteur
Michael Iannotti
  • Fonction : Auteur
Belinda Hall
  • Fonction : Auteur
Katherine Corfield
  • Fonction : Auteur
Anja Paatero
  • Fonction : Auteur
Mark Henderson
  • Fonction : Auteur
Peristera Roboti
  • Fonction : Auteur
Jianhong Zhou
  • Fonction : Auteur
Xianwei Sun
  • Fonction : Auteur
Mugunthan Govindarajan
  • Fonction : Auteur
Jason Rohde
  • Fonction : Auteur
Rachel Simmonds
  • Fonction : Auteur
James Inglese
  • Fonction : Auteur
Yuchun Du
  • Fonction : Auteur
Stephen High
  • Fonction : Auteur
  • PersonId : 870220
Ville Paavilainen
  • Fonction : Auteur
Wei Shi
  • Fonction : Auteur
  • PersonId : 1052602

Résumé

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.
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Dates et versions

hal-02323236 , version 1 (18-12-2019)

Identifiants

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Guanghui Zong, Zhijian Hu, Sarah O’keefe, Dale Tranter, Michael Iannotti, et al.. Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation. Journal of the American Chemical Society, 2019, 141 (21), pp.8450-8461. ⟨10.1021/jacs.8b13506⟩. ⟨hal-02323236⟩
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