Structural insights into RNA cleavage by PIWI Argonaute

Zhiqing Li, Qikui Xu, Jing Zhong, Yan Zhang, Tianxiang Zhang, Xiaoze Ying, Xiaoli Lu, Xiaoyi Li, Li Wan, Junchao Xue, Jing Huang, Ying Zhen, Zhao Zhang, Jianping Wu () and En-Zhi Shen ()
Additional contact information
Zhiqing Li: Westlake University
Qikui Xu: Westlake Laboratory of Life Sciences and Biomedicine
Jing Zhong: Westlake University
Yan Zhang: Westlake University
Tianxiang Zhang: Westlake University
Xiaoze Ying: Westlake University
Xiaoli Lu: Westlake Institute for Advanced Study
Xiaoyi Li: Westlake Laboratory of Life Sciences and Biomedicine
Li Wan: Westlake Laboratory of Life Sciences and Biomedicine
Junchao Xue: Westlake University
Jing Huang: Westlake Laboratory of Life Sciences and Biomedicine
Ying Zhen: Westlake Laboratory of Life Sciences and Biomedicine
Zhao Zhang: Department of Pharmacology and Cancer Biology
Jianping Wu: Westlake Laboratory of Life Sciences and Biomedicine
En-Zhi Shen: Westlake University

Nature, 2025, vol. 639, issue 8053, 250-259

Abstract: Abstract Argonaute proteins are categorized into AGO and PIWI clades. Across most animal species, AGO-clade proteins are widely expressed in various cell types, and regulate normal gene expression1. By contrast, PIWI-clade proteins predominantly function during gametogenesis to suppress transposons and ensure fertility1,2. Both clades use nucleic acid guides for target recognition by means of base pairing, crucial for initiating target silencing, often through direct cleavage. AGO-clade proteins use a narrow channel to secure a tight guide–target interaction3. By contrast, PIWI proteins feature a wider channel that potentially allows mismatches during pairing, broadening target silencing capability4,5. However, the mechanism of PIWI-mediated target cleavage remains unclear. Here we demonstrate that after target binding, PIWI proteins undergo a conformational change from an ‘open’ state to a ‘locked’ state, facilitating base pairing and enhancing target cleavage efficiency. This transition involves narrowing of the binding channel and repositioning of the PIWI-interacting RNA–target duplex towards the MID-PIWI lobe, establishing extensive contacts for duplex stabilization. During this transition, we also identify an intermediate ‘comma-shaped’ conformation, which might recruit GTSF1, a known auxiliary protein that enhances PIWI cleavage activity6. GTSF1 facilitates the transition to the locked state by linking the PIWI domain to the RNA duplex, thereby expediting the conformational change critical for efficient target cleavage. These findings explain the molecular mechanisms underlying PIWI–PIWI-interacting RNA complex function in target RNA cleavage, providing insights into how dynamic conformational changes from PIWI proteins coordinate cofactors to safeguard gametogenesis.

Date: 2025
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DOI: 10.1038/s41586-024-08438-1

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