Structure-guided discovery of ancestral CRISPR-Cas13 ribonucleases

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-07-18 DOI:10.1126/science.adq0553

Peter H. Yoon, Zeyuan Zhang, Kenneth J. Loi, Benjamin A. Adler, Arushi Lahiri, Kamakshi Vohra, Honglue Shi, Daniel Bellieny Rabelo, Marena Trinidad, Ron S. Boger, Muntathar J. Al-Shimary, Jennifer A. Doudna

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Abstract

The RNA-guided ribonuclease CRISPR-Cas13 enables adaptive immunity in bacteria and programmable RNA manipulation in heterologous systems. Cas13s share limited sequence similarity, hindering discovery of related or ancestral systems. To address this, we developed an automated structural-search pipeline to identify an ancestral clade of Cas13 (Cas13an) and further trace Cas13 origins to defense-associated ribonucleases. Despite being one-third the size of other Cas13s, Cas13an mediates robust programmable RNA depletion and defense against diverse bacteriophages. However, unlike its larger counterparts, Cas13an uses a single active site for both CRISPR RNA processing and RNA-guided cleavage, revealing that the ancestral nuclease domain has two modes of activity. Discovery of Cas13an deepens our understanding of CRISPR-Cas evolution and expands opportunities for precision RNA editing, showcasing the promise of structure-guided genome mining.

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在结构指导下发现祖先 CRISPR-Cas13 核糖核酸酶。

RNA 引导的核糖核酸酶 CRISPR-Cas13 可使细菌产生适应性免疫，并在异源系统中实现可编程的 RNA 操作。Cas13的序列相似性有限，阻碍了相关或祖先系统的发现。为了解决这个问题，我们开发了一个自动结构搜索管道，以确定Cas13的一个祖先支系（Cas13an），并进一步追溯Cas13与防御相关的核糖核酸酶的起源。尽管Cas13an的大小只有其他Cas13的三分之一，但它却能介导强大的可编程RNA耗竭和防御各种噬菌体。然而，与较大的同类不同，Cas13an 使用单个活性位点进行 CRISPR RNA 处理和 RNA 引导的裂解，揭示了祖先的核酸酶结构域有两种活动模式。Cas13an的发现加深了我们对CRISPR-Cas进化的理解，扩大了精确RNA编辑的机会，展示了结构引导的基因组挖掘的前景。

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Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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