ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
2 files
0/0

Coibamide A Targets Sec61 to Prevent Biogenesis of Secretory and Membrane Proteins

preprint
submitted on 30.10.2019 and posted on 06.11.2019 by Dale Tranter, Anja Paatero, Shinsaku Kawaguchi, Soheila Kazemi, Jeffrey D. Serrill, Juho Kellosalo, Walter K. Vogel, Uwe Richter, Christopher C. Thornburg, Shinya Oishi, Kerry L. McPhail, Jane E. Ishmael, Ville Paavilainen
Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61α subunit of the trimeric Sec61 translocon. CbA binding to Sec61 results in broad substrate-nonselective inhibition of ER protein import and potent cytotoxicity against specific cancer cell lines. CbA targets a lumenal cavity of Sec61α that is partially shared with known Sec61 inhibitors, yet profiling against resistance conferring Sec61α mutations identified from human HCT116 cells suggests a distinct binding mode for CbA. Specifically, despite conferring strong resistance to all previously known Sec61 inhibitors, the Sec61α mutant R66I remains sensitive to CbA. A further unbiased screen for Sec61α resistance mutations identified the CbA-resistant mutation S71P, which confirms non-identical binding sites for CbA and apratoxin A and supports the susceptibility of the Sec61 plug region for channel inhibition. Remarkably, CbA, apratoxin A andipomoeassin F do not display comparable patterns of potency and selectivity in the NCI60 panel of human cancer cell lines.Our work connecting CbA activity with selective prevention of secretory and membrane protein biogenesis by inhibition of Sec61 opens up possibilities for developing new Sec61 inhibitors with improved drug-like properties that are based on the coibamide pharmacophore.

Funding

Modulation of Protein Biogenesis and Secretion by Natural Product Translocon Ligands

National Institute of General Medical Sciences

Find out more...

Translocational regulation of protein biogenesis

Academy of Finland

Find out more...

History

Email Address of Submitting Author

ville.paavilainen@helsinki.fi

Institution

University of Helsinki, Institute of Biotechnology

Country

Finland

ORCID For Submitting Author

0000-0002-3160-7767

Declaration of Conflict of Interest

No conflict of interest

Exports