Borden Lacy
Last active: 3/24/2020

Structural organization of the functional domains of Clostridium difficile toxins A and B.

Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB
Proc Natl Acad Sci U S A. 2010 107 (30): 13467-72

PMID: 20624955 · PMCID: PMC2922184 · DOI:10.1073/pnas.1002199107

Clostridium difficile toxins A and B are members of an important class of virulence factors known as large clostridial toxins (LCTs). Toxin action involves four major steps: receptor-mediated endocytosis, translocation of a catalytic glucosyltransferase domain across the membrane, release of the enzymatic moiety by autoproteolytic processing, and a glucosyltransferase-dependent inactivation of Rho family proteins. We have imaged toxin A (TcdA) and toxin B (TcdB) holotoxins by negative stain electron microscopy to show that these molecules are similar in structure. We then determined a 3D structure for TcdA and mapped the organization of its functional domains. The molecule has a "pincher-like" head corresponding to the delivery domain and two tails, long and short, corresponding to the receptor-binding and glucosyltransferase domains, respectively. A second structure, obtained at the acidic pH of an endosome, reveals a significant structural change in the delivery and glucosyltransferase domains, and thus provides a framework for understanding the molecular mechanism of LCT cellular intoxication.

MeSH Terms (18)

Animals Bacterial Proteins Bacterial Toxins Binding Sites CHO Cells Clostridium difficile Cricetinae Cricetulus Electrophoresis, Polyacrylamide Gel Enterotoxins Glucosyltransferases Hydrogen-Ion Concentration Mice Mice, Inbred BALB C Microscopy, Electron Models, Molecular Protein Conformation Protein Structure, Tertiary

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