Cholera toxin

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Cholera toxin

Cholera toxin (sometimes abbreviated to CTX, Ctx, or CT) is a protein complex

Protein complex

A multiprotein complex is a group of two or more proteins. Protein complexes are a form of quaternary structure. Proteins in a protein complex are linked by non-covalent protein-protein interactions, and different protein complexes have different degrees of stability over time....
secreted by the bacterium Vibrio cholerae
Vibrio cholerae

Vibrio cholerae is a motile gram negative curved-rod shaped bacterium with a polar flagellum that causes cholera in humans. V. cholerae and other species of the genus Vibrio belong to the gamma subdivision of the Proteobacteria....
. CTX is responsible for the harmful effects of cholera

Cholera

Cholera, sometimes known as Asiatic or epidemic cholera, is an infectious gastroenteritis caused by enterotoxin-producing strains of the bacterium Vibrio cholerae....
infection.

cholera toxin

Exotoxin

An exotoxin is a toxin excreted by a microrganism, including bacterium, fungi, algae, and protozoa. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism....
is an oligomer

Oligomer

In chemistry, an oligomer consists of a limited number of monomer units , in contrast to a polymer which, at least in principle, consists of an unbounded number of monomers....
ic complex made up of six protein subunits: a single copy of the A subunit (part A), and five copies of the B subunit (part B). The two parts are connected by a disulfide bond

Disulfide bond

In chemistry, a disulfide bond is a single covalent bond derived from the coupling of thiol groups. The linkage is also called an SS-bond or disulfide bridge....
.

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Cholera toxin (sometimes abbreviated to CTX, Ctx, or CT) is a protein complex

Protein complex

Cholera

Cholera, sometimes known as Asiatic or epidemic cholera, is an infectious gastroenteritis caused by enterotoxin-producing strains of the bacterium Vibrio cholerae....
infection.

Structure

The cholera toxin

Exotoxin

Oligomer

Disulfide bond

In chemistry, a disulfide bond is a single covalent bond derived from the coupling of thiol groups. The linkage is also called an SS-bond or disulfide bridge....
. The three-dimensional structure of the toxin was determined using X-ray crystallography

X-ray crystallography

X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and scatters into many different directions....
by Zhang et al. in 1995.

The five B subunits—each weighing 12 kDa

Atomic mass unit

The unified atomic mass unit , or dalton or, sometimes, universal mass unit, is a Units of measurement of mass used to express atomic weight and molecular masses....
, 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

Enzyme

Enzymes are biomolecules that catalysis chemical reactions. Almost all enzymes are proteins. In enzymatic reactions, the molecules at the beginning of the process are called Substrate , and the enzyme converts them into different molecules, the products....
payload that ADP-ribosylates

ADP-ribosylation

ADP-ribosylation is a posttranslational modification of proteins that involves the addition of one or more ADP and ribose moieties. These reactions are involved in cell signaling and the control of many cell processes, including DNA repair and apoptosis....
G protein

G protein

G proteins, short for guanine nucleotide-binding proteins, are a family of proteins involved in second messenger cascades.G proteins are so called because they function as "molecular switches," alternating between an inactive guanosine diphosphate and active guanosine triphosphate bound state, ultimately going on to regulate down...
s, while the A2 chain (CTA2, orange) forms an extended alpha helix

Alpha helix

A common motif in the secondary structure of proteins, the alpha helix is a right- or left-handed coiled conformation, resembling a spring , in which every backbone amino group donates a hydrogen bond to the backbone carbonyl group of the amino acid four residues earlier ....
which seats snugly in the central pore of the B subunit ring.

This structure is similar in shape, mechanism, and sequence to the heat-labile enterotoxin

Heat-labile enterotoxin

Heat-labile enterotoxin is a type of Lability toxin found in Escherichia coli.It acts upon adenylate cyclase.References...
secreted by some strains of the Escherichia coli
Escherichia coli

'Escherichia coli' , is a Gram negative bacterium that is commonly found in the lower gastrointestinal tract of warm-blooded animals. Most E....
bacterium.

Mechanism of poisonous action on humans

The pentameric part B of the toxin molecule binds to the surface of the intestinal epithelium

Intestinal epithelium

The intestinal epithelium is the epithelium that covers the small intestine and large intestine. It is simple columnar and Cilia.They primarily take part in the digestive system....
cells. Part A detaches from the pentameric part upon binding, and gets inside the cell via receptor-mediated endocytosis

Endocytosis

Endocytosis is the process by which cell s absorb material from outside the cell by engulfing it with their cell membrane. It is used by all cells of the body because most substances important to them are large Chemical polarity molecules that cannot pass through the hydrophobic plasma membrane or cell membrane....
. Once inside the cell, it permanently ribosylates the Gs alpha subunit

Gs alpha subunit

The Gs alpha subunit is a heterotrimeric G protein subunit which activates adenylate cyclase. Researchers have discovered that a change in the location of this protein in the brain could serve as a biomarker for depression, allowing a simple, rapid, laboratory test to identify patients with depression....
of the heterotrimeric G protein

Heterotrimeric G protein

"G protein" usually refers to the membrane-associated heterotrimeric G proteins, sometimes referred to as the "large" G proteins. These proteins are activated by G protein-coupled receptors and are made up of alpha , beta and GGL domain subunits....
resulting in constitutive cAMP

Cyclic adenosine monophosphate

Cyclic adenosine monophosphate is a second messenger that is important in many biological processes. cAMP is derived from adenosine triphosphate and used for intracellular signal transduction in many different organisms....
production. This in turn leads to secretion of H2O, Na+, K+, Cl-, and HCO3- into the lumen

Lumen

Lumen can mean:* Lumen , the SI unit of luminous flux* Lumen , the cavity or channel within a tubular structure* Thylakoid lumen, the inner membrane space of the chloroplast...
of the small intestine resulting in rapid dehydration

Dehydration

Dehydration is the removal of water from an object. In Physiology terms, it entails a relative deficiency of water molecules in relation to other dissolved solutes....
.

Origin

The gene encoding the cholera toxin is introduced into V. cholerae by horizontal gene transfer

Horizontal gene transfer

Horizontal gene transfer , also Lateral gene transfer , is any process in which an organism incorporates genetic material from another organism without being the Reproduction of that organism....
. Virulent

Virulence

Virulence refers to the degree of pathogenicity of an organism, or in other words the relative ability of a pathogen to cause disease.The word virulent, which is the adjective for virulence, derives from the Latin word virulentus, which means "full of poison." From an ecology point of view, virulence can be defined as the host's p...
strains of V. cholerae carry a variant of lysogenic

Lysogeny

Lysogeny, or the lysogenic cycle, is one of two methods of viral reproduction . Lysogeny in prokaryotes is characterized by integration of the bacteriophage nucleic acid into the host bacterium's genome....
bacteriophage

Bacteriophage

A bacteriophage is any one of a number of viruses that infection bacteria. The term is commonly used in its shortened form, phage.Typically, bacteriophages consist of an outer protein hull enclosing genetic material....
called CTXf or CTXφ.

Synthesis

Once secreted, the B subunit ring of CTX will bind to GM1

GM1

GM1 the "prototype" ganglioside, is a member of the ganglio series of gangliosides which contain one sialic acid residue. GM1 has important physiological properties and impacts Neuroplasticity and repair mechanisms, and the release of neurotrophins in the brain....
ganglioside

Ganglioside

Ganglioside is a compound composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. The 60+ known gangliosides differ mainly in the position and number of NANA residue s....
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.

The CTA1 fragment catalyses ADP ribosylation from NAD to the regulatory component of adenylate cyclase

Adenylate cyclase

Adenylate cyclase is a lyase enzyme....
, thereby activating it. Increased adenylate cyclase

Adenylate cyclase

Adenylate cyclase is a lyase enzyme....
activity increases cyclic AMP (cAMP) synthesis causing massive fluid and electrolyte

Electrolyte

An electrolyte is any substance containing free ions that behaves as an electrical conductor medium. Because they generally consist of ions in solution, electrolytes are also known as ionic solutions, but molten electrolytes and solid electrolytes are also possible....
efflux, resulting in diarrhea

Diarrhea

In medicine, diarrhea, also spelled diarrhoea , is characterized by frequent loose or liquid bowel movements. The spelling of "diarrhea" is an appropriation of the Greek "diarrhoia" meaning "a flowing through." ....
.

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.

GM1 gangliosides are found in lipid raft

Lipid raft

A lipid raft is a cholesterol-enriched microdomain in cell membranes....
s on the cell surface. B subunit complexes labelled with fluorescent tags or subsequently targeted with antibodies can be used to identify rafts.

Cholera toxin

Structure

Mechanism of poisonous action on humans

Origin

Synthesis

Applications

See also

External links