Cholera toxin
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222181181
2008-06-27T23:23:15Z
137.131.130.164
/* Mechanism of action */
[[Image:Cholera Toxin.png|300px|right|thumb|Cholera toxin. the A subunit is red and orange; the B subunit is blue. A portion of the B subunit complex has been rendered partially transparent to show the bound tail of the A2 chain.]]
'''Cholera toxin''' (sometimes abbreviated to '''CTX''', '''Ctx''', or '''CT''') is a [[protein complex]] secreted by the [[bacterium]] ''[[Vibrio cholerae]]''.<ref name=Sherris>{{cite book | author = Ryan KJ; Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | publisher = McGraw Hill | year = 2004 | pages = p. 375 |id = ISBN 0838585299 }}</ref><ref name= FaruqueNair>{{cite book | author = Faruque SM; Nair GB (editors). | title = Vibrio cholerae: Genomics and Molecular Biology | publisher = Caister Academic Press | year = 2008 | url=http://www.horizonpress.com/vib | id = [http://www.horizonpress.com/vib ISBN 978-1-904455-33-2 ]}}</ref> CTX is responsible for the harmful effects of [[cholera]] infection.
==Mechanism of action==
The cholera toxin contains two major parts. The first is a pentameric protein that binds to the surface of the [[intestinal epithelium]]. The second is an [[ADP-ribosylation]] enzyme which ribosylates the [[Gs alpha subunit]] of the [[heterotrimeric G protein]] resulting in constitutive [[cyclic adenosine monophosphate|cAMP]] production. This in turn lead to secretion of chloride and water into the lumen of the intestine resulting in rapid [[dehydration]].
== Structure ==
The cholera [[exotoxin|toxin]] is an [[oligomer]]ic complex made up of six protein subunits: a single copy of the A subunit, and five copies of the B subunit. Its three-dimensional structure was determined using [[X-ray crystallography]] by Zhang ''et al.'' in 1995.<ref name=Zhang_1995>{{cite journal |author=Zhang R, Scott D, Westbrook M, Nance S, Spangler B, Shipley G, Westbrook E |title=The three-dimensional crystal structure of cholera toxin |journal=J Mol Biol |volume=251 |issue=4 |pages=563–73 |year=1995 |pmid=7658473 |doi=10.1006/jmbi.1995.0456}}</ref>
The five B subunits—each weighing 12 [[atomic mass unit|kDa]], and all coloured blue in the accompanying figure—form a five-membered ring. The A subunit has two important segments. The A1 portion of the chain (CTA1, red) is a globular [[enzyme]] payload that [[ADP-ribosylation|ADP-ribosylates]] [[G protein]]s, while the A2 chain (CTA2, orange) forms an extended [[alpha helix]] which seats snugly in the central pore of the B subunit ring.<ref>{{cite journal |author=De Haan L, Hirst TR |title=Cholera toxin: a paradigm for multi-functional engagement of cellular mechanisms (Review) |journal=Mol. Membr. Biol. |volume=21 |issue=2 |pages=77–92 |year=2004 |pmid=15204437 |doi=10.1080/09687680410001663267}}</ref>
This structure is similar in shape, mechanism, and [[protein sequence|sequence]] to the [[heat-labile enterotoxin]] secreted by some strains of the ''[[Escherichia coli]]'' bacterium.
== Origin ==
The gene encoding the cholera toxin is introduced into ''V. cholerae'' by [[horizontal gene transfer]]. [[Virulence|Virulent]] strains of ''V. cholerae'' carry a variant of [[lysogeny|lysogenic]] [[bacteriophage]] called CTXf or CTXφ.<ref name=Davis_2003>{{cite journal |author=Davis B, Waldor M |title=Filamentous phages linked to virulence of Vibrio cholerae |journal=Curr Opin Microbiol |volume=6 |issue=1 |pages=35–42 |year=2003 |pmid=12615217 |doi=10.1016/S1369-5274(02)00005-X}}</ref>
==Synthesis==
Once secreted, the B subunit ring of CTX will bind to [[GM1]] [[ganglioside]]s on the surface of the host's cells. After binding takes place, the entire CTX complex is internalised by the cell and the CTA1 chain is released by the reduction of a [[disulfide bridge]].
CTA1 is then free to bind with a human partner protein called [[ADP-ribosylation factor 6]] (Arf6); binding to Arf6 drives a change in the conformation (the shape) of CTA1 which exposes its active site and enables its catalytic activity.<ref name=O'Neal_2005>{{cite journal |author=O'Neal C, Jobling M, Holmes R, Hol W |title=Structural basis for the activation of cholera toxin by human ARF6-GTP |journal=Science |volume=309 |issue=5737 |pages=1093–6 |year=2005 |pmid=16099990 |doi=10.1126/science.1113398}}</ref>
The CTA1 fragment catalyses ADP ribosylation from NAD to the regulatory component of [[adenylate cyclase]], thereby activating it. Increased [[adenylate cyclase]] activity increases [[cyclic AMP]] (cAMP) synthesis causing massive fluid and [[electrolyte]] efflux, resulting in [[diarrhea]].
== 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 has been used to trace neurons.<ref name="urlThe Discovery of Cholera-Toxin">{{cite web | url = http://sommeil.univ-lyon1.fr/articles/luppi/frenchcorner/sommaire.html | title = The Discovery of Cholera-Toxin as a Powerful Neuroanatomical Tool | author = Pierre-Hervé Luppi | authorlink = | coauthors = | date = | format = | work = | publisher = | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-05-25}}</ref>
GM1 gangliosides are found in [[lipid raft]]s on the cell surface. B subunit complexes labelled with fluorescent tags or subsequently targeted with antibodies can be used to identify rafts.
== See also ==
* [[Enterotoxin]]
== References ==
{{Reflist|2}}
== External links ==
* http://www.ebi.ac.uk/interpro/potm/2005_9/Page1.htm
* [http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb69_1.html Molecule of the Month]
* {{MeshName|Cholera+Toxin}}
{{Glycosyltransferases}}
[[Category:Bacterial proteins]]
[[Category:AB5 toxins]]
[[de:Choleratoxin]]
[[fr:Toxine cholérique]]