Shiga toxin

spinqualitylabelsall models Stx1 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Introduction Shiga Toxins are a family of AB5 toxins (Stx1 and Stx2) which cause dysentery, hemolytic-uremic syndrome, and potentially renal failure in humans. They are primarily secreted by Shiga toxin-encoding Escherichia coli (STEC), notably by the 0157:H7 strain and shigella dysentarie. STECs are one of the major foodborne pathogens, affecting both developed and third-world countries. The stx gene is not endogenous to these strains, but is introduced through horizontal gene transfer from environmental prophages of the lambdoid bacteriophage family and incorporated into the E. Coli genome. Shiga Toxins are closely related to ricin, which is structurally and mechanistically similar. Shiga toxin acts to inhibit protein synthesis in eukaryotic cells and is the main virulence factor of STEC. Human Interaction 0157:H7 STECs are spread to humans through a fecal-oral mechanism, primarily from ingestion of food contaminated with fecal material. Cattle, goats, and sheep are the primary reservoir of STECs and their close proximity to food sources as well as the use of animal feces for fertilizer makes them the main route of contamination. These animals can house STEC's without effect due to a lack of Stx surface receptors. Inadequate sanitation and contamination of meat during slaughter can both lead to STEC contaminated food at the market. Once ingested the STEC can survive the high acid environment of the stomach and progress to the gut where they attach firmly to gut mucosa via the intimin adhesin protein. Secreted Stx then either attacks gut epithelia or passes into the bloodstream where it can damage kidney and brain tissue. Treatments Treatment with antibiotics is contraindicated as antibiotic treatment has been demonstrated to increase Stx production up to one hundred fold. This results from the link between Stx production (and phage induction) to the SOS response pathway. In the event of renal failure kidney dialysis may be employed. A number of potential treatments are under development including B subunit inhibitors, polysaccharides that promote macrophage uptake of Stx, blocking of the Gb3 membrane receptor, and inhibition of retrograde transport. Structure Shiga Toxin consists consists of an AB5 hexamer. The 5 subunit B pentamer interacts with the A subunit via a C-terminal helix of hydrophobic subunits packed antiparallel to 5 B helixes and 4 antiparallel beta sheets.. The glycosidase active site is located on the A subunit, but is blocked by the B subunit until they are cleaved and an active A subunit is released into the target cell. Function Shiga Toxin acts as an N-glycosidase, removing an adenine from the 28S ribosomal rRNA of a target cell which leads to inhibition of protein elongation and ultimately cellular apoptosis. The B subunit is necessary for binding to globo series glycolipid globotriaosylceramide (Gb3), a eukaryotic membrane receptor, where it is then endocytosed and proteolytically cleaved into an active A subunit and a B subunit. The B subunit is not active in the depurination of of 28S rRNA, but is essential for GB3 binding and therefore essential for toxicity. Once in the cytosol the A subunit is free to interact with and inactivate 28S rRNA. On the A subunit Tyr77, Tyr114, Glu167, Arg170, and Trp203 are all essential in glycosidic activity. This mechanism (B subunit binding to globotriaosylceramide and A subunit depurinating 28S rRNA) is conserved amongst the Stx family as well as the ricin toxin.

3D structures

1dm0 - Stx1
1r4q - Stx2
1r4p - Stx2 bound to ligand
2ga4 - Stx2 with adenine

Mutants

1c48 - Shiga-like toxin B subunit
1cqf - Shiga-like toxin B subunit bound to trisaccharide
1bos - Shiga-like toxin bound to receptor

Proteopedia Page Contributors and Editors (what is this?)

Max Evoy-Mount, Michal Harel, Alexander Berchansky