Shiga toxin

From Proteopedia

(Difference between revisions)

Revision as of 10:08, 10 December 2014

1 Introduction
2 Human Interaction
3 Structure
4 Function

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^[1] 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.^[1] 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. For toxins in Proteopedia see Toxins.

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.^[2] These animals can house STEC's without effect due to a lack of Stx surface receptors.^[3] 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.^[4] 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.^[2] This results from the link between Stx production (and phage induction) to the SOS response pathway.^[2] 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.^[5]

Structure

Shiga Toxin consists consists of an AB₅ hexamer.^[6] The via a and .^[6]. The is located on the A subunit, but is blocked by the B subunit until the is cleaved releasing an active A subunit into the target cell.^[6]

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.^[7] 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.^[8] 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 are all essential in glycosidic activity.^[7] 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 of shiga toxin

Updated on 10-December-2014

References

↑ ^1.0 ^1.1 Wagner PL, Livny J, Neely MN, Acheson DW, Friedman DI, Waldor MK. Bacteriophage control of Shiga toxin 1 production and release by Escherichia coli. Mol Microbiol. 2002 May;44(4):957-70. PMID:12010491
↑ ^2.0 ^2.1 ^2.2 Herold S, Karch H, Schmidt H. Shiga toxin-encoding bacteriophages--genomes in motion. Int J Med Microbiol. 2004 Sep;294(2-3):115-21. PMID:15493821
↑ Asakura H, Makino S, Kobori H, Watarai M, Shirahata T, Ikeda T, Takeshi K. Phylogenetic diversity and similarity of active sites of Shiga toxin (stx) in Shiga toxin-producing Escherichia coli (STEC) isolates from humans and animals. Epidemiol Infect. 2001 Aug;127(1):27-36. PMID:11561972
↑ Russell JB, Jarvis GN. Practical mechanisms for interrupting the oral-fecal lifecycle of Escherichia coli. J Mol Microbiol Biotechnol. 2001 Apr;3(2):265-72. PMID:11321582
↑ Nishikawa K. Recent progress of Shiga toxin neutralizer for treatment of infections by Shiga toxin-producing Escherichia coli. Arch Immunol Ther Exp (Warsz). 2011 Aug;59(4):239-47. Epub 2011 Jun 5. PMID:21644029 doi:10.1007/s00005-011-0130-5
↑ ^6.0 ^6.1 ^6.2 Fraser ME, Chernaia MM, Kozlov YV, James MN. Crystal structure of the holotoxin from Shigella dysenteriae at 2.5 A resolution. Nat Struct Biol. 1994 Jan;1(1):59-64. PMID:7656009
↑ ^7.0 ^7.1 Di R, Kyu E, Shete V, Saidasan H, Kahn PC, Tumer NE. Identification of amino acids critical for the cytotoxicity of Shiga toxin 1 and 2 in Saccharomyces cerevisiae. Toxicon. 2011 Mar 15;57(4):525-39. Epub 2010 Dec 22. PMID:21184769 doi:10.1016/j.toxicon.2010.12.006
↑ Roman F, Santa A, Rimanoczky A, Toldi Z, Pataki L. [Isotope study of in vitro K(+) uptake and release of erythrocytes in juvenile diabetes with 86Rb]. Padiatr Grenzgeb. 1990;29(4):339-45. PMID:2170899

Proteopedia Page Contributors and Editors (what is this?)

Max Evoy-Mount, Michal Harel, Alexander Berchansky

Retrieved from "http://52.214.119.220/wiki/index.php/Shiga_toxin"

Category: Topic Page

@@ Line 27: / Line 27: @@
 Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
+{{#tree:id=OrganizedByTopic|openlevels=0|
-[[1dm0]], [[1r4q]] – SdStx α+β chains – ''Shigella dysenteriae''<br />
+*Shiga toxin
-[[4m1u]] – EcStx2 α+β chains + disaccharide – ''Escherichia coli''<br />
-===Shiga-like toxin 1===
+**[[1dm0]], [[1r4q]] – SdStx α+β chains – ''Shigella dysenteriae''<br />
+**[[4m1u]] – EcStx2 α+β chains + disaccharide – ''Escherichia coli''<br />
-[[1czw]], [[1czg]] – pHStx1 β chain (mutant) – phage H30<br />
+*Shiga-like toxin 1
-[[4ull]] – pHStx1 β chain – NMR<br />
-[[1c48]] - pHStx1 β chain receptor-binding domain (mutant)<br />
-[[1bos]], [[1qnu]] – pHStx1 β chain receptor-binding domain + GB3 analog<br />
-[[2xsc]] – EcStx1 β chain <br />
-[[1d1i]], [[1cqf]] – EcStx1 β chain (mutant) + GB3 analog <br />
-[[1c4q]], [[1d1k]] – EcStx1 β chain receptor-binding domain (mutant) + GB3 analog
-===Shiga-like toxin 2===
+**[[1czw]], [[1czg]] – pHStx1 β chain (mutant) – phage H30<br />
+**[[4ull]] – pHStx1 β chain – NMR<br />
+**[[1c48]] - pHStx1 β chain receptor-binding domain (mutant)<br />
+**[[1bos]], [[1qnu]] – pHStx1 β chain receptor-binding domain + GB3 analog<br />
+**[[2xsc]] – EcStx1 β chain <br />
+**[[1d1i]], [[1cqf]] – EcStx1 β chain (mutant) + GB3 analog <br />
+**[[1c4q]], [[1d1k]] – EcStx1 β chain receptor-binding domain (mutant) + GB3 analog
-[[2c5c]] - pHStx2 β chain + inhibitor<br />
+*Shiga-like toxin 2
-[[1r4p]] – EcStx2 α+β chains<br />
-[[3mxg]] – EcStx2 β chain (mutant)<br />
-[[2bos]], [[1qoh]] – EcStx2 β chain receptor-binding domain (mutant) + GB3 analog<br />
-[[2ga4]] - Stx2 α+β chains – enterobacteria phage 933W
+**[[2c5c]] - pHStx2 β chain + inhibitor<br />
+**[[1r4p]] – EcStx2 α+β chains<br />
+**[[3mxg]] – EcStx2 β chain (mutant)<br />
+**[[2bos]], [[1qoh]] – EcStx2 β chain receptor-binding domain (mutant) + GB3 analog<br />
+**[[2ga4]] - Stx2 α+β chains – enterobacteria phage 933W
+}}

Shiga toxin

From Proteopedia

Revision as of 10:08, 10 December 2014

Contents

Introduction

Human Interaction

Structure

Function

3D structures of shiga toxin

References

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