Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon
Decatransin, a new natural product inhibiting protein translocation at the Sec61/SecYEG translocon
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DOI：
10.1242/jcs.165746
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发表时间：
2015-03-15
影响因子：
4
通讯作者：
Hoepfner, Dominic
中科院分区：
文献类型：
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作者：
Junne, Tina;Wong, Joanne;Hoepfner, Dominic
从图拉索毛壳菌中分离得到一种新的环十肽化合物，它对哺乳动物细胞和酵母细胞具有较强的生物活性。酿酒酵母的化学基因组图谱表明，Sec61转位复合体是目标，它是蛋白质转运和内质网膜插入的机制。这些图谱类似于一种不同化学类型的环七肽(包括Hun-7293和辅转素)，先前已被证明抑制哺乳动物Sec61易位子的共翻译易位。在真菌和哺乳动物细胞中进行无偏见的全基因组突变，然后进行全基因组测序，在Sec61p(酵母)或Sec61Alpha 1(哺乳动物)中发现了导致抗药性的显性突变。尽管缺乏结构上的相似性，但大多数但不是所有这些突变都会影响这两种化学类型的抑制作用。生化分析证实，两种化学类型都能抑制共转位底物和翻译后转位底物的蛋白质转位进入内质网，表明了一种独立于翻译核糖体的机制。最有趣的是，这两种化学类型都被发现也抑制细菌Sec61易位基因同源物SecYEG。我们建议将这种新的十肽易位抑制剂命名为“Decatransin”。
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 complex, 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 (including HUN-7293 and 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 (yeast) or Sec61 alpha 1 (mammals) that conferred 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 post-translationally 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 translocon homolog. We suggest 'decatransin' as the name for this new decadepsipeptide translocation inhibitor.