Cholera toxin
Cholera toxin (also known as choleragen and sometimes abbreviated to CTX, Ctx or CT) is an
History
Robert Koch, a German physician and microbiologist, was the first person to postulate the existence of cholera toxin. In 1886, Koch proposed that Vibrio cholerae secreted a substance which caused the symptoms of Cholera.[4] Koch's postulation was proven correct by Indian microbiologist Sambhu Nath De, whom in 1951 studied and documented the effects of injecting rabbits with heat-killed cholerae bacteria.[5] De concluded from this experiment that an endotoxin liberated upon disintegration of the bacteria was the cause of the symptoms of cholera.[5] In 1959, De conducted another experiment, this time using a bactaria-free culture-filtrate from V. Cholera injected into the small intestines of rabbits.[6] The resulting build up of fluid in the intestines conclusively proved the existence of a toxin.[7]
Structure
The complete
The five B subunits—each weighing 11
This structure is similar in shape, mechanism, and
Pathogenesis
Cholera toxin acts by the following mechanism: First, the B subunit ring of the cholera toxin binds to
CTA1 is then free to bind with a human partner protein called
The
Origin
The gene encoding the cholera toxin was introduced into V. cholerae by
Applications
Because the B subunit appears to be relatively non-toxic, researchers have found a number of applications for it in cell and molecular biology. It is routinely used as a
Treatment of cultured rodent neural stem cells with cholera toxin induces changes in the localization of the transcription factor Hes3 and increases their numbers.[19]
GM1 gangliosides are found in lipid rafts on the cell surface. B subunit complexes labelled with fluorescent tags or subsequently targeted with antibodies can be used to identify rafts.
Vaccine
There are currently two vaccines for cholera: Dukoral and Shanchol. Both vaccines use whole killed V. cholerae cells however, Dukoral also contains recombinant cholera toxin β (rCTB). Some studies suggest that the inclusion of rCTB may improve vaccine efficacy in young children (2-10) and increase the duration of protection. This is countered by the costs of protecting and storing rCTB against degradation.[20]
Vaccine adjuvant
Another application of the CTB subunit may be as a vaccine
Membrane biology
Lipid rafts
Since cholera toxin has been shown to preferentially bind to GM1 gangliosides, this characteristic can be utilized for membrane studies. Lipid rafts are difficult to study as they vary in size and lifetime, as well being part of an extremely dynamic component of cells. Using cholera toxin β as a marker, we can get a better understanding of the properties and functions of lipid rafts.[21]
Endocytosis
Endocytosis is broadly divided into clathrin-dependent and clathrin-independent process, and the cholera toxin utilizes both pathways. Cholera toxin has been shown to enter cells via endocytosis in multiple pathways. These pathways include caveolae, clathrin-coated pits, clathrin-independent carriers (CLICs), and GPI-Enriched Endocytic Compartments (GEECs) pathway, ARF6-mediated endocytosis and Fast Endophilin-Mediated Endocytosis (FEME). How cholera toxin triggers these endocytosis pathways is not fully understood, but the fact that cholera toxin triggers these pathways shows the use of the toxin as an important marker to investigate these mechanisms.[21]
Retrograde trafficking
One of the most important aspects of cholera toxin is the retrograde traffic mechanism that transports the toxin from the cell membrane back to the trans-Golgi network and the endoplasmic reticulum. Since both cholera toxin and GM1 species can be tagged with a fluorescent tags, the mechanism of retrograde traffic can be monitored. This opens up the potential to monitor the mechanism in real time. This may open up new discoveries on how intracellular transport works and how protein and lipid sorting work in the endocytotic pathway.[21]
See also
References
- ISBN 978-0-8385-8529-0.
- ISBN 978-1-904455-33-2.
- S2CID 33657660.
- PMID 21415492.
- ^ PMID 14898376.
- PMID 13666809.
- PMID 21415492.
- PMID 7658473.
- S2CID 22270979.
- PMID 26512888.
- PMID 29432456.
- PMID 29411974.
- S2CID 3111310.
- S2CID 8669389.
- ^ Joaquín Sánchez; Jan Holmgren (February 2011). "Cholera toxin – A foe & a friend" (PDF). Indian Journal of Medical Research. 133: 158. Archived from the original (PDF) on 2013-02-03. Retrieved 2013-06-09.
- ^ Boron, W. F., & Boulpaep, E. L. (2009). Medical physiology: a cellular and molecular approach (2nd ed.). Philadelphia, Pennsylvania: Saunders/Elsevier.
- ^ ISSN 1369-5274.
- ^ Pierre-Hervé Luppi. "The Discovery of Cholera-Toxin as a Powerful Neuroanatomical Tool". Retrieved 2011-03-23.
- PMID 20520777.
- ^ PMID 25802972.
- ^ PMID 34437414.
External links
- De, Sambhu Nath. Enterotoxicity of bacteria-free culture filtrate of Vibrio cholerae. Nature. 30 May 1959. 183:1533–4.
- McDowall, Jennifer (Sep 2005). "Cholera toxin". Protein of the Month (POTM). Protein Data Bank in Europe (PDBe). Archived from the original on April 27, 2019.
- Goodsell, David (Sep 2005). "Cholera Toxin". RCSB Protein Data Bank. Molecule of the Month (MOTM). Protein Data Bank (PDB). from the original on October 25, 2011.
- Cholera+Toxin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P01555 (Cholera enterotoxin subunit A) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: P01556 (Cholera enterotoxin subunit B) at the PDBe-KB.