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Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon

Junne, Tina and Wong, Joanne and Studer, Christian and Aust, Thomas and Bauer, Benedikt W. and Beibel, Martin and Bhullar, Bhupinder and Bruccoleri, Robert and Eichenberger, Jürg and Estoppey, David and Hartmann, Nicole and Knapp, Britta and Krastel, Philipp and Melin, Nicolas and Oakeley, Edward J. and Oberer, Lukas and Riedl, Ralph and Roma, Guglielmo and Schuierer, Sven and Petersen, Frank and Tallarico, John A. and Rapoport, Tom A. and Spiess, Martin and Hoepfner, Dominic. (2015) Decatransin, a novel natural product inhibiting protein translocation at the Sec61/SecY translocon. Journal of Cell Science, 128 (6). pp. 1217-1229.

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Official URL: http://edoc.unibas.ch/dok/A6357884

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Abstract

A new cyclic decadepsipeptide was isolated from Chaetosphaeria tulasneorum with potent bioactivity on mammalian and yeast cells. Chemogenomic profiling in S. cerevisiae indicated that the Sec61 translocon, the machinery for protein translocation and membrane insertion at the endoplasmic reticulum, is the target. The profiles were similar to those of cyclic heptadepsipeptides of a distinct chemotype (HUN-7293/cotransin) that had previously been shown to inhibit cotranslational translocation at the mammalian Sec61 translocon. Unbiased, genome-wide mutagenesis followed by full-genome sequencing in both fungal and mammalian cells identified dominant mutations in Sec61p/Sec61α1 to confer resistance. Most, but not all, of these mutations affected inhibition by both chemotypes, despite an absence of structural similarity. Biochemical analysis confirmed inhibition of protein translocation into the endoplasmic reticulum of both co- and posttranslationally translocated substrates by both chemotypes, demonstrating a mechanism independent of a translating ribosome. Most interestingly, both chemotypes were found to also inhibit SecYEG, the bacterial Sec61 homolog. We suggest "decatransin" as the name for this novel decadepsipeptide translocation inhibitor.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Spiess)
UniBasel Contributors:Spiess, Martin
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Company of Biologists
ISSN:0021-9533
e-ISSN:1477-9137
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:09 Nov 2017 15:54
Deposited On:10 Apr 2015 09:12

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