Prokaryotes have evolved diverse defense strategies against viral infection, such as foreign nucleic acid degradation by CRISPR-Cas systems and DNA/RNA synthesis inhibition via nucleotide pool depletion. Here, we report an antiviral mechanism of type III CRISPR-Cas-regulated ATP depletion, where ATP is converted into ITP by CRISPR-Cas-associated adenosine deaminase (CAAD) upon activation by either cA 4 or cA 6 , followed by hydrolysis into IMP by Nudix hydrolase, ultimately resulting in cell growth arrest. The cryo-electron microscopy structures of CAAD in its apo and activated forms, together with biochemical evidence, revealed how cA 4 /cA 6 binds to the CARF domain and abrogates CAAD autoinhibition, inducing substantial conformational changes that reshape the structure of CAAD and induce its deaminase activity. Our results reveal the mechanism of a CRISPR-Cas-regulated ATP depletion antiviral strategy.

中文翻译：

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III 型 CRISPR 相关脱氨酶的抗病毒信号


原核生物已经进化出多种针对病毒感染的防御策略，例如通过 CRISPR-Cas 系统降解外源核酸和通过核苷酸库耗竭抑制 DNA/RNA 合成。在这里，我们报道了 III 型 CRISPR-Cas 调节的 ATP 耗竭的抗病毒机制，其中 ATP 在被 cA 4 或 cA 6 激活后被 CRISPR-Cas 相关腺苷脱氨酶 （CAAD） 转化为 ITP，然后被 Nudix 水解酶水解成 IMP，最终导致细胞生长停滞。CAAD 的载脂蛋白和活化形式的冷冻电子显微镜结构，以及生化证据，揭示了 cA 4 /cA 6 如何与 CARF 结构域结合并消除 CAAD 自抑制，诱导实质性的构象变化，重塑 CAAD 的结构并诱导其脱氨酶活性。我们的结果揭示了 CRISPR-Cas 调节的 ATP 耗竭抗病毒策略的机制。