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

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.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC10730571 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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

Zhou Yao Y Zhan Xiechao X Luo Jianhua J Li Diyin D Zhou Ruoyu R Zhang Jiahao J Pan Zhenrui Z Zhang Yuanyuan Y Jia Tianhui T Zhang Xiaofeng X Li Yanyan Y Tao Liang L

Nature communications 20231219 1

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 neut ...[more]

PMID: 38114525

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Project description:BackgroundWith the current rise of antibiotic resistance in bacteria, it is important to monitor the efficacy of antimicrobials in clinical use. Paeniclostridium sordellii (previously Clostridium sordellii) is a bacterial pathogen that causes human uterine infection after spontaneous or medically induced abortion, for which mortality rates approach 100%. Prophylactic antibiotics have been recommended for individuals undergoing medically-induced abortion, one of which is doxycycline, a member of the tetracycline antibiotic family. However, tetracycline resistance had not been well characterized in P. sordellii. This study therefore aimed to determine the levels of tetracycline resistance in P. sordellii isolates, and to identify associated loci and their genomic locations.ResultsUsing a MIC assay, five of 24 P. sordellii isolates were found to be resistant to tetracycline, minocycline, and importantly, doxycycline. Analysis of genome sequence data from 46 isolates found that phenotypically resistant isolates encoded a variant of the Clostridium perfringens tetracycline resistance determinant Tet P. Bioinformatic analysis and comparison of the regions surrounding these determinants found variation in the genomic location of Tet P among P. sordellii isolates. The core genome comparison of the 46 isolates revealed genetic diversity and the absence of dominant genetic types among the isolates. There was no strong association between geographic location of isolation, animal host or Tet P carriage with isolate genetic type. Furthermore, the analysis of the Tet P genotype revealed that Tet P is encoded chromosomally, or on one of two, novel, small plasmids, all consistent with multiple acquisition and recombination events. BLAST analysis of Clostridioides difficile draft genome sequences also identified a Tet P locus, the genomic location of which demonstrated an evolutionary relationship with the P. sordellii locus.ConclusionsThe Tet P determinant is found in variable genomic locations within diverse human and animal isolates of P. sordellii and C. difficile, which suggests that it can undergo horizontal transfer, and may disseminate tetracycline resistance between clostridial species. Doxycycline is a suggested prophylactic treatment for P. sordellii infections, however, a small sub-set of the isolates tested are resistant to this antibiotic. Doxycycline may therefore not be an appropriate prophylactic treatment for P. sordellii infections.

Dataset Information

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

Publications

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

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