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
{"title":"在结构指导下发现祖先 CRISPR-Cas13 核糖核酸酶。","authors":"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","doi":"10.1126/science.adq0553","DOIUrl":null,"url":null,"abstract":"<div >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.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"385 6708","pages":""},"PeriodicalIF":44.7000,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Structure-guided discovery of ancestral CRISPR-Cas13 ribonucleases\",\"authors\":\"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\",\"doi\":\"10.1126/science.adq0553\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >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.</div>\",\"PeriodicalId\":21678,\"journal\":{\"name\":\"Science\",\"volume\":\"385 6708\",\"pages\":\"\"},\"PeriodicalIF\":44.7000,\"publicationDate\":\"2024-07-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/science.adq0553\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/science.adq0553","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Structure-guided discovery of ancestral CRISPR-Cas13 ribonucleases
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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