美国斯隆凯特林研究所Christopher D. Lima研究组发现人核外泌体靶向 (NEXT) 复合物是RNA 监测的结构基础。相关论文于2022年6月9日发表于国际顶尖学术期刊《细胞》杂志上。

他们确定了与 RNA 结合的人核外泌体靶向 (NEXT) 复合物的冷冻电镜结构，揭示了对底物识别和 RNA 移交给外泌体之前的早期步骤的机制见解。这些结构将 ZCCHC8 用作支架，介导同源二聚化，同时环抱MTR4 解旋酶并将 RBM7 灵活地锚定到解旋酶核心。所有三个亚基协同结合 RNA、RBM7 和 ZCCHC8 测量 3' 端上游的序列以促进 MTR4 捕获 RNA。

ZCCHC8 掩盖了对 RNA 结合和挤出以及 MPP6 依赖性募集和与 RNA 外泌体核心对接很重要的 MTR4 表面，这些相互作用通过协调 RNA 捕获、易位和从解旋酶到外泌体的挤出以进行衰变来促进 RNA 监视。

研究人员表示，RNA 质量控制依赖于辅助因子和接头来识别和准备底物，以供核糖核酸酶降解，例如 3' 到 5' 核糖核酸外泌体。

附：英文原文

Title: Structural basis for RNA surveillance by the human nuclear exosome targeting (NEXT) complex

Author: M. Rhyan Puno, Christopher D. Lima

Issue&Volume: 2022/06/09

Abstract: RNA quality control relies on co-factors and adaptors to identify and prepare substrates for degradation by ribonucleases such as the 3′ to 5′ ribonucleolytic RNA exosome. Here, we determined cryogenic electron microscopy structures of human nuclear exosome targeting (NEXT) complexes bound to RNA that reveal mechanistic insights to substrate recognition and early steps that precede RNA handover to the exosome. The structures illuminate ZCCHC8 as a scaffold, mediating homodimerization while embracing the MTR4 helicase and flexibly anchoring RBM7 to the helicase core. All three subunits collaborate to bind the RNA, with RBM7 and ZCCHC8 surveying sequences upstream of the 3′ end to facilitate RNA capture by MTR4. ZCCHC8 obscures MTR4 surfaces important for RNA binding and extrusion as well as MPP6-dependent recruitment and docking onto the RNA exosome core, interactions that contribute to RNA surveillance by coordinating RNA capture, translocation, and extrusion from the helicase to the exosome for decay.

DOI: 10.1016/j.cell.2022.04.016

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00463-9