Structural basis of subtilase cytotoxin subAB assembly

Le Nours, J., Paton, A., Byres, E., Troy, S., Herdman, B., Johnson, M., Paton, J., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 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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Abstract

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:	28 Oct 2022 09:53
URI:	https://orca.cardiff.ac.uk/id/eprint/76032

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