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Structure and mechanism of a Type III CRISPR defence DNA nuclease activated by cyclic oligoadenylate.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-019-14222-x Stephen A McMahon 1 , Wenlong Zhu 1 , Shirley Graham 1 , Robert Rambo 2 , Malcolm F White 1 , Tracey M Gloster 1
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-019-14222-x Stephen A McMahon 1 , Wenlong Zhu 1 , Shirley Graham 1 , Robert Rambo 2 , Malcolm F White 1 , Tracey M Gloster 1
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The CRISPR system provides adaptive immunity against mobile genetic elements in prokaryotes. On binding invading RNA species, Type III CRISPR systems generate cyclic oligoadenylate (cOA) signalling molecules, potentiating a powerful immune response by activating downstream effector proteins, leading to viral clearance, cell dormancy or death. Here we describe the structure and mechanism of a cOA-activated CRISPR defence DNA endonuclease, CRISPR ancillary nuclease 1 (Can1). Can1 has a unique monomeric structure with two CRISPR associated Rossman fold (CARF) domains and two DNA nuclease-like domains. The crystal structure of the enzyme has been captured in the activated state, with a cyclic tetra-adenylate (cA4) molecule bound at the core of the protein. cA4 binding reorganises the structure to license a metal-dependent DNA nuclease activity specific for nicking of supercoiled DNA. DNA nicking by Can1 is predicted to slow down viral replication kinetics by leading to the collapse of DNA replication forks.
中文翻译：
环状寡聚腺苷酸激活的III型CRISPR防御DNA核酸酶的结构和机制。
CRISPR系统提供针对原核生物中移动遗传元件的适应性免疫。在结合入侵的RNA物种时，III型CRISPR系统产生环状寡聚腺苷酸（cOA）信号分子，通过激活下游效应蛋白来增强强大的免疫反应，从而导致病毒清除，细胞休眠或死亡。在这里，我们描述了cOA激活的CRISPR防御DNA核酸内切酶CRISPR辅助核酸酶1（Can1）的结构和机制。Can1具有独特的单体结构，具有两个CRISPR相关的Rossman折叠（CARF）结构域和两个DNA核酸酶样结构域。酶的晶体结构已被激活状态捕获，环状四腺苷酸（cA4）分子结合在蛋白质的核心。cA4结合重组了结构，以许可对超螺旋DNA形成切口特异性的金属依赖性DNA核酸酶活性。预计Can1产生的DNA切口会导致DNA复制叉崩溃，从而减慢病毒复制动力学。
更新日期：2020-01-24
中文翻译：
环状寡聚腺苷酸激活的III型CRISPR防御DNA核酸酶的结构和机制。
CRISPR系统提供针对原核生物中移动遗传元件的适应性免疫。在结合入侵的RNA物种时，III型CRISPR系统产生环状寡聚腺苷酸（cOA）信号分子，通过激活下游效应蛋白来增强强大的免疫反应，从而导致病毒清除，细胞休眠或死亡。在这里，我们描述了cOA激活的CRISPR防御DNA核酸内切酶CRISPR辅助核酸酶1（Can1）的结构和机制。Can1具有独特的单体结构，具有两个CRISPR相关的Rossman折叠（CARF）结构域和两个DNA核酸酶样结构域。酶的晶体结构已被激活状态捕获，环状四腺苷酸（cA4）分子结合在蛋白质的核心。cA4结合重组了结构，以许可对超螺旋DNA形成切口特异性的金属依赖性DNA核酸酶活性。预计Can1产生的DNA切口会导致DNA复制叉崩溃，从而减慢病毒复制动力学。
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