近日，韩国首尔大学教授Soung-Hun Roh及其团队提出了分子伴侣引导RNA诱导沉默复合物组装的结构基础。相关论文于2026年6月10日发表在《自然》杂志上。

在这里，该团队鉴定了人类AGO–HSP90–p23复合物，它捕获无RNA状态的AGO，称为AGO成熟复合物（AMC）。纯化的AMC能够进行RNA装载和AGO折叠，忠实地再现从头开始的RISC组装。利用低温电子显微镜，课题组确定了与microRNA双链结合的AMC的结构。与其在RISC中的构象相反，AGO在AMC中采用高度开放的构象：N结构域和RNA结合模块（PAZ-MID-PIWI）完全分离并锚定在HSP90二聚体的两侧，仅由未展开的L1连接子连接。这种排列暴露出一个带正电的间隙，可以容纳RNA双工。AGO折叠是由含有5'端磷酸的小RNA双工促进的，而不是单链RNA，这揭示了RNA双工作为伴侣样的辅助因子的作用，指导AGO结构域的组装。这些发现阐明了RISC组装机制，并建立了AMC作为探索最佳RNA特征和化学修饰的分子工具，以合理设计小干扰RNA疗法。他们的研究还揭示了伴侣蛋白是如何与配体一起指导客户蛋白折叠的。

据悉，RNA诱导沉默复合体（RISC）由一个Argonaute （AGO）蛋白和一个小RNA组成，是RNA沉默的核心效应物。小RNA在依赖HSP70和HSP90的过程中以大体积双链的形式装载到AGO上，但其分子机制尚不清楚。

附：英文原文

Title: Structural basis for chaperone-guided assembly of RNA-induced silencing complex

Author: Lee, Young-Yoon, Jeong, Minseok, Lee, Hansol, Lee, Daniel, Lee, Jaehyun, Park, Junsun, Kim, V. Narry, Roh, Soung-Hun

Issue&Volume: 2026-06-10

Abstract: The RNA-induced silencing complex (RISC), comprising an Argonaute (AGO) protein and a small RNA, is the central effector in RNA silencing. Small RNAs are loaded onto AGO as bulky duplexes in an HSP70- and HSP90-dependent process1,2,3, but the molecular mechanism remains poorly understood. Here we identify the human AGO–HSP90–p23 complex, which captures AGO in an RNA-free state, termed the AGO maturation complex (AMC). The purified AMC enables RNA loading and AGO folding, faithfully recapitulating de novo RISC assembly. Using cryogenic electron microscopy, we determined the structure of AMC bound to a microRNA duplex. In contrast to its conformation in the RISC, AGO adopts a highly open conformation in the AMC: the N domain and the RNA-binding module (PAZ–MID–PIWI) are fully detached and anchored to opposite sides of the HSP90 dimer, connected solely by the unfolded L1 linker. This arrangement exposes a positively charged cleft that accommodates an RNA duplex. AGO folding is facilitated by a small RNA duplex containing a 5′-terminal phosphate—but not by single-stranded RNAs—revealing a role for the RNA duplex as a chaperone-like cofactor that directs AGO domain assembly. These findings elucidate the RISC assembly mechanism and establish the AMC as a molecular tool for probing optimal RNA features and chemical modifications for the rational design of small interfering RNA therapeutics. Our study also sheds light on how chaperones, together with ligands, can guide the folding of client proteins.

DOI: 10.1038/s41586-026-10640-2

Source: https://www.nature.com/articles/s41586-026-10640-2