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Structural basis of subtilase cytotoxin subAB assembly

Le Nours, J., Paton, A., Byres, E., Troy, S., Herdman, B., Johnson, M., Paton, J., Rossjohn, Jamie and Beddoe, T. 2013. Structural basis of subtilase cytotoxin subAB assembly. Journal of Biological Chemistry 288 (38) , pp. 27505-27516. 10.1074/jbc.M113.462622

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Pathogenic strains of Escherichia coli produce a number of toxins that belong to the AB5 toxin family, which comprise a catalytic A-subunit that induces cellular dysfunction and a B-pentamer that recognizes host glycans. Although the molecular actions of many of the individual subunits of AB5 toxins are well understood, how they self-associate and the effect of this association on cytotoxicity are poorly understood. Here we have solved the structure of the holo-SubAB toxin that, in contrast to other AB5 toxins whose molecular targets are located in the cytosol, cleaves the endoplasmic reticulum chaperone BiP. SubA interacts with SubB in a similar manner to other AB5 toxins via the A2 helix and a conserved disulfide bond that joins the A1 domain with the A2 helix. The structure revealed that the active site of SubA is not occluded by the B-pentamer, and the B-pentamer does not enhanceorinhibit the activity of SubA. Structure-based sequence comparisons with other AB5 toxin family members, combined with extensive mutagenesis studies on SubB, show how the hydrophobic patch on top of the B-pentamer plays a dominant role in binding the A-subunit. The structure of SubAB and the accompanying functional characterization of various mutants of SubAB provide a framework for understanding the important role of the B-pentamer in the assembly and the intracellular trafficking of this AB5 toxin.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Uncontrolled Keywords: Cellular dysfunction; Endoplasmic reticulum chaperone; Functional characterization; Hydrophobic patch; Intracellular trafficking; Molecular targets; Pathogenic strains; Sequence comparisons;Bacterial Toxins; Disulfides; Escherichia coli; Escherichia coli Proteins; Mutagenesis; Protein Structure, Quaternary; Protein Structure, Tertiary; Protein Transport; Structure-Activity Relationship; Subtilisins
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Last Modified: 04 Jun 2017 08:20

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