The structural landscape of Microprocessor-mediated processing of pri-let-7 miRNAs

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2024-10-04 DOI:10.1016/j.molcel.2024.09.008

Ankur Garg, Renfu Shang, Todor Cvetanovic, Eric C. Lai, Leemor Joshua-Tor

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Abstract

MicroRNA (miRNA) biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by the Microprocessor (MP), composed of the Drosha RNase III enzyme and its partner DGCR8. Multiple pri-miRNA sequence motifs affect MP recognition, fidelity, and efficiency. Here, we performed cryoelectron microscopy (cryo-EM) and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has the structural plasticity to accommodate a range of pri-miRNAs. These structures revealed key features of the 5′ UG sequence motif, more comprehensively represented as the “flipped U with paired N” (fUN) motif. Our analysis explains how cleavage of class-II pri-let-7 members harboring a bulged nucleotide generates a non-canonical precursor with a 1-nt 3′ overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 contributes to MP fidelity by interacting with the CNNC motif and Drosha’s Piwi/Argonaute/Zwille (PAZ)-like domain. Overall, this study sheds light on the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP.

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微处理器介导的 pri-let-7 miRNA 处理结构图

由 Drosha RNase III 酶及其伙伴 DGCR8 组成的微处理器（MP）对初级 miRNA（pri-miRNA）发夹进行切割后，就开始了微 RNA（miRNA）的生物生成。多种 pri-miRNA 序列基序会影响 MP 的识别、保真度和效率。在这里，我们对几种与人类 MP 复合的 let-7 家族 pri-miRNA 进行了冷冻电子显微镜（cryo-EM）和生化研究。我们发现 MP 具有结构可塑性，可以容纳一系列 pri-miRNA。这些结构揭示了 5′ UG 序列基序的关键特征，更全面地表述为 "带成对 N 的翻转 U"（fUN）基序。我们的分析解释了携带凸起核苷酸的 II 类 pri-let-7 成员如何通过裂解产生具有 1-nt 3′ 悬垂的非经典前体。最后，MP-SRSF3-pri-let-7f1结构揭示了SRSF3如何通过与CNNC基序和Drosha的Piwi/Argonaute/Zwille（PAZ）样结构域相互作用来促进MP的保真度。总之，这项研究揭示了 MP 灵活识别、准确切割和调控处理不同 pri-miRNA 的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.