Journal
Cell Chemical Biology
Volume 23, Issue 5, Pages 561-566Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2016.04.008
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Funding
- Academy of Finland [289737]
- Sigrid Juselius Foundation
- Biocentrum Helsinki
- US NIH [NS059690, CA100851]
- Howard Hughes Medical Institute
- Academy of Finland (AKA) [289737, 289737] Funding Source: Academy of Finland (AKA)
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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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