中国科学院邓增钦研究小组取得一项新突破。他们报道了ATP酶-核酸酶双酶抗噬菌体防御复合物的分子和结构基础。2024年6月4日出版的《细胞研究》杂志发表了这项成果。

据悉，在细菌免疫应答中，偶联不同的酶效应物作为防御噬菌体感染的有效策略出现，例如在III型CRISPR-Cas系统中广泛研究的核酸酶和环化酶活性。然而，协同酶在其他细菌防御系统中的活性却知之甚少。

研究组对双组分防御系统DUF4297–HerA进行了生化和结构表征，证明DUF4297–HerA通过协同切割dsDNA和水解ATP来抵抗噬菌体感染。DUF4297单独形成二聚体，HerA单独以非平面分裂螺旋六聚体存在，两者都表现出极低的酶活性。有趣的是，DUF4297和HerA组装成一个大约1MDa的超分子复合物，其中两层DUF4297(每层6个DUF4297分子)通过相邻DUF4297分子的层间二聚化，而堆叠在HerA六聚体的顶部。

重要的是，复合物组装促进了上层DUF4297分子的二聚化，并使HerA从非平面六聚体过渡到平面六聚体，从而激活它们各自的酶活性来消除噬菌体感染。总之，他们的发现不仅表征了一种新的双酶抗噬菌体防御系统，而且揭示了细菌免疫中通过合作复合物组装的独特激活机制。

附：英文原文

Title: Molecular and structural basis of an ATPase-nuclease dual-enzyme anti-phage defense complex

Author: An, Qiyin, Wang, Yong, Tian, Zhenhua, Han, Jie, Li, Jinyue, Liao, Fumeng, Yu, Feiyang, Zhao, Haiyan, Wen, Yancheng, Zhang, Heng, Deng, Zengqin

Issue&Volume: 2024-06-04

Abstract: Coupling distinct enzymatic effectors emerges as an efficient strategy for defense against phage infection in bacterial immune responses, such as the widely studied nuclease and cyclase activities in the type III CRISPR-Cas system. However, concerted enzymatic activities in other bacterial defense systems are poorly understood. Here, we biochemically and structurally characterize a two-component defense system DUF4297–HerA, demonstrating that DUF4297–HerA confers resistance against phage infection by cooperatively cleaving dsDNA and hydrolyzing ATP. DUF4297 alone forms a dimer, and HerA alone exists as a nonplanar split spiral hexamer, both of which exhibit extremely low enzymatic activity. Interestingly, DUF4297 and HerA assemble into an approximately 1 MDa supramolecular complex, where two layers of DUF4297 (6 DUF4297 molecules per layer) linked via inter-layer dimerization of neighboring DUF4297 molecules are stacked on top of the HerA hexamer. Importantly, the complex assembly promotes dimerization of DUF4297 molecules in the upper layer and enables a transition of HerA from a nonplanar hexamer to a planar hexamer, thus activating their respective enzymatic activities to abrogate phage infection. Together, our findings not only characterize a novel dual-enzyme anti-phage defense system, but also reveal a unique activation mechanism by cooperative complex assembly in bacterial immunity.

DOI: 10.1038/s41422-024-00981-w

Source: https://www.nature.com/articles/s41422-024-00981-w