Shiga Toxin (Stx) Classification, Structure, and Function

Abstract

Shiga toxin (Stx) is one of the most potent bacterial toxins known. Stx is found in Shigella dysenteriae 1 and in some serogroups of Escherichia coli (called Stx1 in E. coli). In addition to or instead of Stx1, some E. coli 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 E. coli, 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.

Figure 1. 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 A₁ subunit and the A₂ 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.

Figure 2. Ribbon diagram of the Stx1 crystal structure

The B pentamer is shown in orange and the A₂ in blue. The majority of the A₁ 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 A₂ 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.

Figure 3. 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 A₁ tethered to A₂B5 is reduced. The A₁ chain then enters the cytosol and removes an adenine residue from the 28S ribosome.