Apratoxin Kills Cells by Direct Blockade of the Sec61 Protein Translocation Channel
Apratoxin Kills Cells by Direct Blockade of the Sec61 Protein Translocation Channel
复制标题
DOI：
10.1016/j.chembiol.2016.04.008
复制
发表时间：
2016-05-19
影响因子：
8.6
通讯作者：
Paavilainen, Ville O.
中科院分区：
文献类型：
--
作者：
Paatero, Anja O.;Kellosalo, Juho;Paavilainen, Ville O.
Apratoxin A是一种细胞毒性天然产物，可阻止分泌蛋白和膜蛋白的生物合成。在生物化学上，黄曲霉毒素A抑制共翻译移位进入ER，但其细胞靶点和作用机制仍然存在争议。在这里，我们证明，黄曲霉毒素A防止蛋白质易位直接针对Sec61 α，中央亚基的蛋白质易位通道。诱变和竞争性光交联研究表明，阿曲毒素A结合Sec61的侧门的方式，从cotransin，底物选择性Sec61抑制剂不同。与cotransin相反，阿曲毒素A不表现出底物选择性抑制机制，但以相似的效力阻断所有测试的Sec61客户的ER易位。我们的研究结果表明，多种结构上不相关的天然产物已经进化到靶向Sec61上重叠但不相同的结合位点，从而产生不同的生物学结果。
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.