Structural dynamics of the CROPs domain control stability and toxicity of Paeniclostridium sordellii lethal toxin

Yao Zhou, Xiechao Zhan (), Jianhua Luo, Diyin Li, Ruoyu Zhou, Jiahao Zhang, Zhenrui Pan, Yuanyuan Zhang, Tianhui Jia, Xiaofeng Zhang, Yanyan Li and Liang Tao ()
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Yao Zhou: Westlake Laboratory of Life Sciences and Biomedicine
Xiechao Zhan: Westlake Laboratory of Life Sciences and Biomedicine
Jianhua Luo: Westlake Laboratory of Life Sciences and Biomedicine
Diyin Li: Westlake Laboratory of Life Sciences and Biomedicine
Ruoyu Zhou: Westlake Laboratory of Life Sciences and Biomedicine
Jiahao Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Zhenrui Pan: Westlake Laboratory of Life Sciences and Biomedicine
Yuanyuan Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Tianhui Jia: Westlake Laboratory of Life Sciences and Biomedicine
Xiaofeng Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Yanyan Li: Westlake Laboratory of Life Sciences and Biomedicine
Liang Tao: Westlake Laboratory of Life Sciences and Biomedicine

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Paeniclostridium sordellii lethal toxin (TcsL) is a potent exotoxin that causes lethal toxic shock syndrome associated with fulminant bacterial infections. TcsL belongs to the large clostridial toxin (LCT) family. Here, we report that TcsL with varied lengths of combined repetitive oligopeptides (CROPs) deleted show increased autoproteolysis as well as higher cytotoxicity. We next present cryo-EM structures of full-length TcsL, at neutral (pH 7.4) and acidic (pH 5.0) conditions. The TcsL at neutral pH exhibits in the open conformation, which resembles reported TcdB structures. Low pH induces the conformational change of partial TcsL to the closed form. Two intracellular interfaces are observed in the closed conformation, which possibly locks the cysteine protease domain and hinders the binding of the host receptor. Our findings provide insights into the structure and function of TcsL and reveal mechanisms for CROPs-mediated modulation of autoproteolysis and cytotoxicity, which could be common across the LCT family.

Date: 2023
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DOI: 10.1038/s41467-023-44169-z

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