Inhibition of eukaryotic translation initiation by the marine natural product pateamine A
Inhibition of eukaryotic translation initiation by the marine natural product pateamine A
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DOI：
10.1016/j.molcel.2005.10.008
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发表时间：
2005-12-09
期刊：
影响因子：
16
通讯作者：
Liu, JO
中科院分区：
文献类型：
--
作者：
Low, WK;Dang, YJ;Liu, JO
真核生物的翻译起始是通过包括eIF4起始因子在内的大量蛋白质的协调有序作用来完成的。在此，我们报道了帕特胺A(PATA)，一种有效的抗增殖和促凋亡的海洋天然产物，抑制了帽子依赖的真核细胞翻译启动。PATA结合并增强eIF4A的内源性酶活性，但抑制eIF4A与eIF4G的结合，促进eIF4A与eIF4B形成稳定的三元复合体。当eIF4A与PATA结合时，其伴侣蛋白与eIF4A亲和力的变化在体外导致了mRNA上的起始复合体的停滞，并在体内诱导了应激颗粒的形成。这些结果表明，PATA将是未来真核生物翻译起始研究的一个有价值的分子探针，并可能作为抗癌药物开发的先导化合物。
Translation initiation in eukaryotes is accomplished through the coordinated and orderly action of a large number of proteins, including the eIF4 initiation factors. Herein, we report that pateamine A (PatA), a potent anti proliferative and proapoptotic marine natural product, inhibits cap-dependent eukaryotic translation initiation. PatA bound to and enhanced the intrinsic enzymatic activities of eIF4A, yet it inhibited eIF4A-eIF4G association and promoted the formation of a stable ternary complex between eIF4A and eIF4B. These changes in eIF4A affinity for its partner proteins upon binding to PatA caused the stalling of initiation complexes on mRNA in vitro and induced stress granule formation in vivo. These results suggest that PatA will be a valuable molecular probe for future studies of eukaryotic translation initiation and may serve as a lead compound for the development of anticancer agents.