Crystal structure of the eIF4A-PDCD4 complex
Crystal structure of the eIF4A-PDCD4 complex
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DOI：
10.1073/pnas.0808275106
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发表时间：
2009-03-03
影响因子：
11.1
通讯作者：
Cho, Yunje
中科院分区：
文献类型：
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作者：
Chang, Jeong Ho;Cho, Yong Hyun;Cho, Yunje
肿瘤抑制因子程序性细胞死亡蛋白4 （PDCD4）抑制翻译起始因子eIF4A， eIF4A是一种RNA解旋酶，催化mrna的5'-非翻译区二级结构解绕并控制翻译起始。在这里，我们确定了人类eIF4A和PDCD4复合物的晶体结构。该结构揭示了PDCD4分子通过两种不同的结合模式与两个eIF4A分子结合。当PDCD4的两个MA3结构域与一个eIF4A分子结合时，同一PDCD4的c端MA3结构域也与另一个eIF4A分子相互作用。eIF4A-PDCD4复合体结构表明，PDCD4的MA3结构域与eIF4A两个结构域的界面垂直结合，阻止了eIF4A结构域的关闭，并阻断了RNA与eIF4A的结合，这两者都是eIF4A解旋酶功能中必需的事件。该结构与生化分析一起揭示了PDCD4对eIF4A的抑制机制，并为设计靶向eIF4A的化学物质提供了框架。
Tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5'-untranslated region of mRNAs and controls the initiation of translation. Here, we determined the crystal structure of the human eIF4A and PDCD4 complex. The structure reveals that one molecule of PDCD4 binds to the two eIF4A molecules through the two different binding modes. While the two MA3 domains of PDCD4 bind to one eIF4A molecule, the C-terminal MA3 domain alone of the same PDCD4 also interacts with another eIF4A molecule. The eIF4A-PDCD4 complex structure suggests that the MA3 domain(s) of PDCD4 binds perpendicular to the interface of the two domains of eIF4A, preventing the domain closure of eIF4A and blocking the binding of RNA to eIF4A, both of which are required events in the function of eIF4A helicase. The structure, together with biochemical analyses, reveals insights into the inhibition mechanism of eIF4A by PDCD4 and provides a framework for designing chemicals that target eIF4A.