[cell系列] 1月12日，《细胞》(Cell)杂志发表了中国科学院生物物理研究所王艳丽课题组关于Ⅵ型CRISPR- Cas系统的效应蛋白C2c2的结构研究。标题为Two Distant Catalytic Sites Are Responsible for C2c2 RNase Activities。该研究解析了Leptotrichiashahii (Lsh)细菌中C2c2与crRNA (CRISPR-RNA)的二元复合物以及C2c2在自由状态下的晶体结构，揭示了LshC2c2通过两个独立的活性结构域来发挥其两种不同的RNA酶切活性，这为研究C2c2发挥RNA酶活性的分子机制提供了重要的结构生物学基础。
王艳丽课题组通过深入的研究，解析了C2c2与crRNA的二元复合物的晶体结构以及C2c2蛋白的晶体结构，揭示了C2c2包含一个crRNA识别的叶片即REC叶片，和一个核酸酶叶片即NUC叶片。REC叶片包含NTD结构域(N-terminal domain)和Helical-1结构域，NUC叶片包含了两个HEPN结构域、Helical-2结构域以及连接两个HEPN结构域的连接结构域。负责切割前体crRNA和靶标RNA的活性口袋分别位于Helical-1和HEPN结构域上。crRNA的结合会引起C2c2蛋白的构象变化，这种变化很可能会稳定crRNA的结合，进而对识别靶标RNA起着重要作用。该研究通过结构和生化研究揭示了C2c2剪切pre-crRNA以及切割靶标RNA的分子机制，对认识细菌抵抗RNA病毒入侵的分子基础具有十分重要的意义。同时也为改造CRISPR-C2c2系统，为其在基因编辑领域的运用提供了强有力的结构基础，有助于加速对病毒感染引发的疾病的理解、治疗和预防。
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C2c2, the effector of type VI CRISPR-Cas systems, has two RNase activities—one for cutting its RNA target and the other for processing the CRISPR RNA (crRNA). Here, we report the structures of Leptotrichiashahii C2c2 in its crRNA- free and crRNA-bound states. While C2c2 has a bilobed structure reminiscent of all other Class 2 effectors, it also exhibits different structural characteristics. It contains the REC lobe with a Helical-1 domain and the NUC lobe with two HEPN domains. The two RNase catalytic pockets responsible for cleaving pre-crRNA and target RNA are independently located on Helical-1 and HEPN domains, respectively. crRNA binding induces significant conformational changes that are likely to stabilize crRNA binding and facilitate target RNA recognition. These structures provide important insights into the molecular mechanism of dual RNase activities of C2c2 and establish a framework for its future engineering as a RNA editing tool.