Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation
Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation
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DOI：
10.1038/nsmb.2855
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发表时间：
2014-08-01
影响因子：
16.8
通讯作者：
Sattler, Michael
中科院分区：
文献类型：
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作者：
Schlundt, Andreas;Heinz, Gitta A.;Sattler, Michael
T细胞中的Roquin功能对于预防自身免疫性疾病至关重要。Roquin与共刺激受体的3'非翻译区（UTRs）相互作用，控制t细胞的激活和分化。本研究表明，小鼠roquin的n端ROQ结构域采用延长的翼状螺旋（WH）折叠，足以结合Tnf 3' UTR中的本构衰变元件（CDE）。具有典型CDE RNA茎环复合物的ROQ结构域的晶体结构揭示了RNA茎及其三环的紧密识别。令人惊讶的是，roquin主要使用非序列特异性的RNA接触，从而表明CDE共识较为宽松，并暗示目标mrna的范围比先前预期的更广。与此一致的是，核磁共振和CDE样茎环结合实验以及基于细胞的分析证实了自然3' utr中松弛CDE共识基序的roquin依赖性调节。
Roquin function in T cells is essential for the prevention of autoimmune disease. Roquin interacts with the 3' untranslated regions (UTRs) of co-stimulatory receptors and controls T-cell activation and differentiation. Here we show that the N-terminal ROQ domain from mouse roquin adopts an extended winged-helix (WH) fold, which is sufficient for binding to the constitutive decay element (CDE) in the Tnf 3' UTR. The crystal structure of the ROQ domain in complex with a prototypical CDE RNA stem-loop reveals tight recognition of the RNA stem and its triloop. Surprisingly, roquin uses mainly non-sequence-specific contacts to the RNA, thus suggesting a relaxed CDE consensus and implicating a broader spectrum of target mRNAs than previously anticipated. Consistently with this, NMR and binding experiments with CDE-like stem-loops together with cell-based assays confirm roquin-dependent regulation of relaxed CDE consensus motifs in natural 3' UTRs.