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核孔蛋白和 InsP6 通过保守机制激活 DEAD-box ATP 酶促进 mRNA 输出。

A conserved mechanism of DEAD-box ATPase activation by nucleoporins and InsP6 in mRNA export.

机构信息

Division of Cell and Developmental Biology, University of California, Berkeley, California 94720, USA.

出版信息

Nature. 2011 Apr 14;472(7342):238-42. doi: 10.1038/nature09862. Epub 2011 Mar 27.

DOI:10.1038/nature09862
PMID:21441902
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3078754/
Abstract

Superfamily 1 and superfamily 2 RNA helicases are ubiquitous messenger-RNA-protein complex (mRNP) remodelling enzymes that have critical roles in all aspects of RNA metabolism. The superfamily 2 DEAD-box ATPase Dbp5 (human DDX19) functions in mRNA export and is thought to remodel mRNPs at the nuclear pore complex (NPC). Dbp5 is localized to the NPC via an interaction with Nup159 (NUP214 in vertebrates) and is locally activated there by Gle1 together with the small-molecule inositol hexakisphosphate (InsP(6)). Local activation of Dbp5 at the NPC by Gle1 is essential for mRNA export in vivo; however, the mechanistic role of Dbp5 in mRNP export is poorly understood and it is not known how Gle1(InsP6) and Nup159 regulate the activity of Dbp5. Here we report, from yeast, structures of Dbp5 in complex with Gle1(InsP6), Nup159/Gle1(InsP6) and RNA. These structures reveal that InsP(6) functions as a small-molecule tether for the Gle1-Dbp5 interaction. Surprisingly, the Gle1(InsP6)-Dbp5 complex is structurally similar to another DEAD-box ATPase complex essential for translation initiation, eIF4G-eIF4A, and we demonstrate that Gle1(InsP6) and eIF4G both activate their DEAD-box partner by stimulating RNA release. Furthermore, Gle1(InsP6) relieves Dbp5 autoregulation and cooperates with Nup159 in stabilizing an open Dbp5 intermediate that precludes RNA binding. These findings explain how Gle1(InsP6), Nup159 and Dbp5 collaborate in mRNA export and provide a general mechanism for DEAD-box ATPase regulation by Gle1/eIF4G-like activators.

摘要

超家族 1 和超家族 2 RNA 解旋酶是普遍存在的信使 RNA-蛋白复合物 (mRNP) 重塑酶，在 RNA 代谢的各个方面都具有关键作用。超家族 2 DEAD -box ATP 酶 Dbp5（人 DDX19）在 mRNA 输出中起作用，被认为在核孔复合物 (NPC) 处重塑 mRNP。Dbp5 通过与 Nup159（脊椎动物中的 NUP214）相互作用而定位在 NPC 上，并在 NPC 处被 Gle1 与小分子肌醇六磷酸 (InsP(6)) 局部激活。Gle1 在 NPC 处对 Dbp5 的局部激活对于体内 mRNA 输出至关重要；然而，Dbp5 在 mRNP 输出中的作用机制尚不清楚，也不知道 Gle1(InsP6) 和 Nup159 如何调节 Dbp5 的活性。在这里，我们从酵母中报告了 Dbp5 与 Gle1(InsP6)、Nup159/Gle1(InsP6) 和 RNA 复合物的结构。这些结构表明 InsP(6) 作为 Gle1-Dbp5 相互作用的小分子连接物。令人惊讶的是，Gle1(InsP6)-Dbp5 复合物在结构上类似于另一种 DEAD-box ATP 酶复合物，对于翻译起始至关重要，eIF4G-eIF4A，我们证明 Gle1(InsP6) 和 eIF4G 都通过刺激 RNA 释放来激活它们的 DEAD-box 伴侣。此外，Gle1(InsP6) 解除 Dbp5 的自我调节，并与 Nup159 合作稳定阻止 RNA 结合的开放 Dbp5 中间产物。这些发现解释了 Gle1(InsP6)、Nup159 和 Dbp5 如何在 mRNA 输出中协作，并为 Gle1/eIF4G 样激活剂对 DEAD-box ATP 酶的调节提供了一般机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/27fc3051ae75/nihms266350f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/be4b353d08b6/nihms266350f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/abd095ffad21/nihms266350f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/e7cd81153c79/nihms266350f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/27fc3051ae75/nihms266350f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/be4b353d08b6/nihms266350f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/abd095ffad21/nihms266350f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/e7cd81153c79/nihms266350f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cb8/3078754/27fc3051ae75/nihms266350f4.jpg

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