Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6XA, UK.
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK.
Nat Commun. 2018 Feb 26;9(1):831. doi: 10.1038/s41467-018-03182-3.
Exosomal miRNA transfer is a mechanism for cell-cell communication that is important in the immune response, in the functioning of the nervous system and in cancer. Syncrip/hnRNPQ is a highly conserved RNA-binding protein that mediates the exosomal partition of a set of miRNAs. Here, we report that Syncrip's amino-terminal domain, which was previously thought to mediate protein-protein interactions, is a cryptic, conserved and sequence-specific RNA-binding domain, designated NURR (N-terminal unit for RNA recognition). The NURR domain mediates the specific recognition of a short hEXO sequence defining Syncrip exosomal miRNA targets, and is coupled by a non-canonical structural element to Syncrip's RRM domains to achieve high-affinity miRNA binding. As a consequence, Syncrip-mediated selection of the target miRNAs implies both recognition of the hEXO sequence by the NURR domain and binding of the RRM domains 5' to this sequence. This structural arrangement enables Syncrip-mediated selection of miRNAs with different seed sequences.
外泌体 miRNA 转移是一种细胞间通讯的机制，在免疫反应、神经系统功能和癌症中都很重要。Syncrip/hnRNPQ 是一种高度保守的 RNA 结合蛋白，介导一组 miRNA 的外泌体分配。在这里，我们报告说，Syncrip 的氨基末端结构域，以前被认为介导蛋白质-蛋白质相互作用，是一个隐藏的、保守的和序列特异性的 RNA 结合结构域，命名为 NURR（RNA 识别的 N 端单元）。NURR 结构域介导对短 hEXO 序列的特异性识别，该序列定义了 Syncrip 外泌体 miRNA 靶标，并且通过非典型结构元件与 Syncrip 的 RRM 结构域偶联，以实现高亲和力的 miRNA 结合。因此，Syncrip 介导的靶 miRNA 的选择意味着 NURR 结构域对 hEXO 序列的识别以及 RRM 结构域对该序列 5'端的结合。这种结构排列使 Syncrip 能够选择具有不同种子序列的 miRNA。
