人 DROSHA 的结构。

Structure of Human DROSHA.

机构信息

Center for RNA Research, Institute for Basic Science, Seoul 08826, Korea; School of Biological Sciences, Seoul National University, Seoul 08826, Korea.

Department of Physics and Astronomy, Seoul National University, Seoul 08826, Korea; National Center for Creative Research Initiatives, Seoul National University, Seoul 08826, Korea; Institute of Applied Physics, Seoul National University, Seoul 08826, Korea.

出版信息

Cell. 2016 Jan 14;164(1-2):81-90. doi: 10.1016/j.cell.2015.12.019. Epub 2015 Dec 31.

DOI:10.1016/j.cell.2015.12.019

PMID:26748718

Abstract

MicroRNA maturation is initiated by RNase III DROSHA that cleaves the stem loop of primary microRNA. DROSHA functions together with its cofactor DGCR8 in a heterotrimeric complex known as Microprocessor. Here, we report the X-ray structure of DROSHA in complex with the C-terminal helix of DGCR8. We find that DROSHA contains two DGCR8-binding sites, one on each RNase III domain (RIIID), which mediate the assembly of Microprocessor. The overall structure of DROSHA is surprisingly similar to that of Dicer despite no sequence homology apart from the C-terminal part, suggesting that DROSHA may have evolved from a Dicer homolog. DROSHA exhibits unique features, including non-canonical zinc-finger motifs, a long insertion in the first RIIID, and the kinked link between Connector helix and RIIID, which explains the 11-bp-measuring "ruler" activity of DROSHA. Our study implicates the evolutionary origin of DROSHA and elucidates the molecular basis of Microprocessor assembly and primary microRNA processing.

摘要

miRNA 的成熟是由 RNase III DROSHA 切割初级 miRNA 的茎环结构启动的。DROSHA 与其辅助因子 DGCR8 一起在称为 Microprocessor 的异三聚体复合物中发挥作用。在这里，我们报告了 DROSHA 与 DGCR8 的 C 端螺旋形成复合物的 X 射线结构。我们发现 DROSHA 包含两个 DGCR8 结合位点，分别位于每个 RNase III 结构域（RIIID）上，介导 Microprocessor 的组装。尽管除了 C 端部分外没有序列同源性，但 DROSHA 的整体结构与 Dicer 惊人地相似，表明 DROSHA 可能是从 Dicer 同源物进化而来的。DROSHA 表现出独特的特征，包括非典型的锌指模体、第一 RIIID 中的长插入以及连接环与 RIIID 之间的扭曲连接，这解释了 DROSHA 的 11 个碱基测量“标尺”活性。我们的研究提示了 DROSHA 的进化起源，并阐明了 Microprocessor 组装和初级 miRNA 加工的分子基础。