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

• Published in: Nature communications 2023-12, Vol.14 (1), p.8426-8426, Article 8426
• Main Authors: Zhou, Yao, Zhan, Xiechao, Luo, Jianhua, Li, Diyin, Zhou, Ruoyu, Zhang, Jiahao, Pan, Zhenrui, Zhang, Yuanyuan, Jia, Tianhui, Zhang, Xiaofeng, Li, Yanyan, Tao, Liang
• Format: Article
• Language: English
• Subjects: 101/28; 101/58; 13/51; 14/63; 42/70; 631/326/41/1319; 631/535/1258/1259; 64/60; 82/80; 82/83; Bacterial diseases; Bacterial Toxins - metabolism; Clostridioides difficile - metabolism; Clostridium sordellii - chemistry; Clostridium sordellii - metabolism; Conformation; Control stability; Crops; Cysteine proteinase; Cytotoxicity; Domains; Dynamic stability; Exotoxins; Exotoxins - metabolism; Humanities and Social Sciences; Metalloproteases - metabolism; multidisciplinary; Oligopeptides; Paeniclostridium sordellii; pH effects; Science; Science (multidisciplinary); Septic shock; Structure-function relationships; Toxic shock syndrome; Toxicity; Toxins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44169-z

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. Paeniclostridium sordellii lethal toxin (TcsL) is a potent toxin that can cause toxic shock syndrome. TcsL contains a unique CROPs domain with unclear functions. Here, the authors provide evidence of the CROPs domain’s role in stability and toxicity of TcsL.