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Apratoxin kills cells by direct blockade of the sec61 protein translocation channel

TitleApratoxin kills cells by direct blockade of the sec61 protein translocation channel
Publication TypeJournal Article
Year of Publication2016
AuthorsPaatero A.O, Kellosalo J., Dunyak B.M, Almaliti J., Gestwicki J.E, Gerwick WH, Taunton J., Paavilainen V.O
JournalCell Chemical Biology
Date Published2016/05
Type of ArticleArticle
ISBN Number2451-9448
Accession NumberWOS:000381508700008
Keywordscotranslational translocation; cyclodepsipeptide; endoplasmic-reticulum; er membrane; mechanisms; pathway; potent

Apratoxin A is a cytotoxic natural product that prevents the biogenesis of secretory and membrane proteins. Biochemically, apratoxin A inhibits cotranslational translocation into the ER, but its cellular target and mechanism of action have remained controversial. Here, we demonstrate that apratoxin A prevents protein translocation by directly targeting Sec61 alpha, the central subunit of the protein translocation channel. Mutagenesis and competitive photo-crosslinking studies indicate that apratoxin A binds to the Sec61 lateral gate in a manner that differs from cotransin, a substrate-selective Sec61 inhibitor. In contrast to cotransin, apratoxin A does not exhibit a substrate-selective inhibitory mechanism, but blocks ER translocation of all tested Sec61 clients with similar potency. Our results suggest that multiple structurally unrelated natural products have evolved to target overlapping but non-identical binding sites on Sec61, thereby producing distinct biological outcomes.

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