1. School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia
2. Protein Crystallography Unit and ARC Centre of Excellence in Structural and Functional Microbial Genomics, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
3. Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA

Correspondence to: Adrienne W. Paton¹James C. Paton¹ Correspondence and requests for materials should be addressed to A.W.P. (Email: adrienne.paton@adelaide.edu.au) or J.C.P. (Email: james.paton@adelaide.edu.au). The coordinates and structure factors for SubA have been deposited in the Protein Data Bank and assigned the deposition code 2iy9.

Abstract

AB₅ toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB₅ toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli. Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.