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

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 enz...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-07, Vol.107 (30), p.13467-13472
Main Authors: Pruitt, Rory N., Chambers, Melissa G., Ng, Kenneth K.-S., Ohi, Melanie D., Lacy, D. Borden, Harrison, Stephen C.
Format: Article
Language:English
Subjects:
Animals
Bacterial Proteins - chemistry
Bacterial Proteins - ultrastructure
Bacterial Toxins - chemistry
Binding Sites
Biological Sciences
CHO Cells
Clostridium difficile
Clostridium difficile - metabolism
Cricetinae
Cricetulus
Crystal structure
Drunkenness
Electron microscopy
Electrophoresis, Polyacrylamide Gel
Endocytosis
endosomes
Enterotoxins - chemistry
Formates
Functional morphology
Glucosyltransferase
Glucosyltransferases - chemistry
Glucosyltransferases - metabolism
Head
Hydrogen-Ion Concentration
Intoxication
Membranes
Mice
Mice, Inbred BALB C
Microscopy, Electron
Models, Molecular
Molecular modelling
Molecular structure
Molecules
Neutral particles
pH effects
Protein Conformation
Protein Structure, Tertiary
Proteins
Receptors
Stains
Toxin A
Toxin B
Toxins
Translocation
virulence factors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1002199107