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Appears in Collections:Biological and Environmental Sciences Journal Articles
Peer Review Status: Refereed
Title: Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS
Authors: Albesa-Jove, David
Bertrand, Thomas
Carpenter, Elisabeth P
Swain, Gemma V
Lim, Jenson
Zhang, Jiancheng
Haire, Lesley F
Vasisht, Nishi
Braun, Veit
Lange, Anton
von, Eichel-Streiber Christoph
Svergun, Dmitri I
Fairweather, Neil F
Brown, Katherine A
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Keywords: Clostridium difficile
toxin B
domain boundaries
Issue Date: 12-Mar-2010
Publisher: Elsevier
Citation: Albesa-Jove D, Bertrand T, Carpenter EP, Swain GV, Lim J, Zhang J, Haire LF, Vasisht N, Braun V, Lange A, von Eichel-Streiber C, Svergun DI, Fairweather NF & Brown KA (2010) Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS, Journal of Molecular Biology, 396 (5), pp. 1260-1270.
Abstract: Clostridium difficile is a nosocomial bacterial pathogen causing antibiotic-associated diarrhea and fatal pseudomembranous colitis. Key virulence factors are toxin A and toxin B (TcdB), two highly related toxins that are members of the large clostridial toxin family. These large multifunctional proteins disrupt cell function using a glucosyltransferase domain that is translocated into the cytosol after vesicular internalization of intact holotoxin. Although substantial information about the biochemical mechanisms of intoxication exists, research has been hampered by limited structural information, particularly of intact holotoxin. Here, we used small-angle X-ray scattering (SAXS) methods to obtain an ab initio low-resolution structure of native TcdB, which demonstrated that this molecule is monomeric in solution and possesses a highly asymmetric shape with a maximum dimension of approximately 275 A. Combining this SAXS information with crystallographic or modeled structures of individual functional domains of TcdB reveals for the first time that the three-dimensional structure of TcdB is organized into four distinct structural domains. Structures of the N-terminal glucosyltransferase, the cysteine protease, and the C-terminal repeat region can be aligned within three domains of the SAXS envelope. A fourth domain, predicted to be involved in the translocation of the glucosyltransferase, appears as a large solvent-exposed protrusion. Knowledge of the shapes and relative orientations of toxin domains provides new insight into defining functional domain boundaries and provides a framework for understanding how potential intra-domain interactions enable conformational changes to propagate between domains to facilitate intoxication processes.
Type: Journal Article
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Rights: The publisher does not allow this work to be made publicly available in this Repository. Please use the Request a Copy feature at the foot of the Repository record to request a copy directly from the author. You can only request a copy if you wish to use this work for your own research or private study.
Affiliation: Imperial College London
Imperial College London
Imperial College London
Imperial College London
Biological and Environmental Sciences
Imperial College London
MRC National Institute for Medical Research
MRC National Institute for Medical Research
Johannes Gutenberg University of Mainz
European Molecular Biology Laboratory
Imperial College London
Imperial College London

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