A CAF40-binding motif facilitates recruitment of the CCR4-NOT complex to mRNAs targeted by Drosophila Roquin.
A CAF40-binding motif facilitates recruitment of the CCR4-NOT complex to mRNAs targeted by Drosophila Roquin.
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DOI：
10.1038/ncomms14307
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发表时间：
2017-02-06
影响因子：
16.6
通讯作者：
Izaurralde E
中科院分区：
文献类型：
--
作者：
Sgromo A;Raisch T;Bawankar P;Bhandari D;Chen Y;Kuzuoğlu-Öztürk D;Weichenrieder O;Izaurralde E
人(HS)Roqu1和Roqu2是RNA结合蛋白，通过CCR4-Not Deadenylase复合体的募集促进mRNA靶向降解，并参与预防自身免疫。Roqu1招募CCR4-不是通过在Roqu2或无脊椎动物Roquin中不保守的C-末端区域。在这里，我们表明Roqu2和果蝇黑腹果蝇Roquin也通过它们的C-末端区域与CCR4相互作用--不是复合体。DM Roquin的C-末端区域包含多个介导CCR4-非结合的基序。一个基序与CCR4的CAF40亚基结合--而不是复合体。DM Roquin CAF40结合基序(CBM)的晶体结构表明，CBM与CAF40的保守表面结合后，呈α-螺旋构象。因此，尽管缺乏序列保守，Roquin蛋白的C-末端区域仍然作为一个效应结构域，通过招募CCR4-NOT复合体来抑制mRNA靶标的表达。Roquin蛋白通过招募效应分子，如CCR4-而不是死烯基酶复合体，下调靶mRNA的表达。在这里，作者提供了Roquin蛋白如何招募CCR4--而不是抑制其靶标表达的复合体的分子细节。
Human (Hs) Roquin1 and Roquin2 are RNA-binding proteins that promote mRNA target degradation through the recruitment of the CCR4-NOT deadenylase complex and are implicated in the prevention of autoimmunity. Roquin1 recruits CCR4-NOT via a C-terminal region that is not conserved in Roquin2 or in invertebrate Roquin. Here we show that Roquin2 and Drosophila melanogaster (Dm) Roquin also interact with the CCR4-NOT complex through their C-terminal regions. The C-terminal region of Dm Roquin contains multiple motifs that mediate CCR4-NOT binding. One motif binds to the CAF40 subunit of the CCR4-NOT complex. The crystal structure of the Dm Roquin CAF40-binding motif (CBM) bound to CAF40 reveals that the CBM adopts an α-helical conformation upon binding to a conserved surface of CAF40. Thus, despite the lack of sequence conservation, the C-terminal regions of Roquin proteins act as an effector domain that represses the expression of mRNA targets via recruitment of the CCR4-NOT complex. Roquin proteins downregulate target mRNA expression by recruiting effectors such as the CCR4-NOT deadenylase complex. Here the authors provide molecular details of how Roquin proteins recruit the CCR4-NOT complex to repress the expression of its targets.