Structural basis for the non-self RNA-activated protease activity of the type III-E CRISPR nuclease-protease Craspase

Ning Cui, Jun-Tao Zhang, Zhuolin Li, Xiao-Yu Liu, Chongyuan Wang, Hongda Huang () and Ning Jia ()
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Ning Cui: Southern University of Science and Technology
Jun-Tao Zhang: Southern University of Science and Technology
Zhuolin Li: Southern University of Science and Technology
Xiao-Yu Liu: Southern University of Science and Technology
Chongyuan Wang: Chinese Academy of Science
Hongda Huang: Southern University of Science and Technology
Ning Jia: Southern University of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract The RNA-targeting type III-E CRISPR-gRAMP effector interacts with a caspase-like protease TPR-CHAT to form the CRISPR-guided caspase complex (Craspase), but their functional mechanism is unknown. Here, we report cryo-EM structures of the type III-E gRAMPcrRNA and gRAMPcrRNA-TPR-CHAT complexes, before and after either self or non-self RNA target binding, and elucidate the mechanisms underlying RNA-targeting and non-self RNA-induced protease activation. The associated TPR-CHAT adopted a distinct conformation upon self versus non-self RNA target binding, with nucleotides at positions −1 and −2 of the CRISPR-derived RNA (crRNA) serving as a sensor. Only binding of the non-self RNA target activated the TPR-CHAT protease, leading to cleavage of Csx30 protein. Furthermore, TPR-CHAT structurally resembled eukaryotic separase, but with a distinct mechanism for protease regulation. Our findings should facilitate the development of gRAMP-based RNA manipulation tools, and advance our understanding of the virus-host discrimination process governed by a nuclease-protease Craspase during type III-E CRISPR-Cas immunity.

Date: 2022
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DOI: 10.1038/s41467-022-35275-5

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