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Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13467-72. doi: 10.1073/pnas.1002199107. Epub 2010 Jul 12.

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

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1
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Abstract

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.

PMID:
20624955
PMCID:
PMC2922184
DOI:
10.1073/pnas.1002199107
[Indexed for MEDLINE]
Free PMC Article
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