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Shiga Toxin (Stx) Classification, Structure, and Function

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  • Author: Angela R. Melton-Celsa1
  • Editors: Vanessa Sperandio2, Carolyn J. Hovde3
    Affiliations: 1: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; 2: University of Texas Southwestern Medical Center, Dallas, TX; 3: University of Idaho, Moscow, ID
  • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
  • Received 14 January 2014 Accepted 03 February 2014 Published 31 July 2014
  • Angela R. Melton-Celsa, [email protected]
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  • Abstract:

    Shiga toxin (Stx) is one of the most potent bacterial toxins known. Stx is found in 1 and in some serogroups of (called Stx1 in ). In addition to or instead of Stx1, some strains produce a second type of Stx, Stx2, that has the same mode of action as Stx/Stx1 but is antigenically distinct. Because subtypes of each toxin have been identified, the prototype toxin for each group is now designated Stx1a or Stx2a. The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits. The A subunit of the toxin injures the eukaryotic ribosome and halts protein synthesis in target cells. The function of the B pentamer is to bind to the cellular receptor, globotriaosylceramide, Gb3, found primarily on endothelial cells. The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum. In humans infected with Stx-producing , the most serious manifestation of the disease, hemolytic-uremic syndrome, is more often associated with strains that produce Stx2a rather than Stx1a, and that relative toxicity is replicated in mice and baboons. Stx1a and Stx2a also exhibit differences in cytotoxicity to various cell types, bind dissimilarly to receptor analogs or mimics, induce differential chemokine responses, and have several distinctive structural characteristics.

  • Citation: Melton-Celsa A. 2014. Shiga Toxin (Stx) Classification, Structure, and Function. Microbiol Spectrum 2(4):EHEC-0024-2013. doi:10.1128/microbiolspec.EHEC-0024-2013.


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Shiga toxin (Stx) is one of the most potent bacterial toxins known. Stx is found in 1 and in some serogroups of (called Stx1 in ). In addition to or instead of Stx1, some strains produce a second type of Stx, Stx2, that has the same mode of action as Stx/Stx1 but is antigenically distinct. Because subtypes of each toxin have been identified, the prototype toxin for each group is now designated Stx1a or Stx2a. The Stxs consist of two major subunits, an A subunit that joins noncovalently to a pentamer of five identical B subunits. The A subunit of the toxin injures the eukaryotic ribosome and halts protein synthesis in target cells. The function of the B pentamer is to bind to the cellular receptor, globotriaosylceramide, Gb3, found primarily on endothelial cells. The Stxs traffic in a retrograde manner within the cell, such that the A subunit of the toxin reaches the cytosol only after the toxin moves from the endosome to the Golgi and then to the endoplasmic reticulum. In humans infected with Stx-producing , the most serious manifestation of the disease, hemolytic-uremic syndrome, is more often associated with strains that produce Stx2a rather than Stx1a, and that relative toxicity is replicated in mice and baboons. Stx1a and Stx2a also exhibit differences in cytotoxicity to various cell types, bind dissimilarly to receptor analogs or mimics, induce differential chemokine responses, and have several distinctive structural characteristics.

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Cartoon representation of the Stx structure. The active-site glutamic acid is indicated as a vertical blue line, the ribosome interaction region is shown in purple, the protease (furin)- sensitive site is depicted in green, and the B pentamer as an orange block. The disulfide bridge that connects the A subunit and the A peptide is shown above the protease-sensitive site. A region important for translocation from the ER to the cytosol is indicated by a bracket. Not to scale.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
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Ribbon diagram of the Stx1 crystal structure. The B pentamer is shown in orange and the A in blue. The majority of the A is depicted in green except for the region that interacts with the ribosome, which is shown in purple. The active residue 167 is red, and other active-site side chains are pale blue. The A chain is medium blue, and the B subunits are orange. The structure (1R4Q) was drawn with PyMOL Molecular Graphics System, Version 1.5.0, Schrödinger, LLC. Figure kindly provided by Dr. James Vergis.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
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An illustration of the retrograde pathway for Stxs. The toxin binds to Gb3 within lipid rafts that contain cholesterol and that complex is internalized within an endosome. From the endosome the toxin traffics to the Golgi where it is nicked by furin if that nicking did not occur in the intestine. The nicked toxin moves to the ER where the disulfide bridge that keeps the A tethered to AB5 is reduced. The A chain then enters the cytosol and removes an adenine residue from the 28S ribosome.

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013
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Prototype toxins and strains that produce those toxins

Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.EHEC-0024-2013

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