Sandbox Reserved 492

This Sandbox is Reserved from 13/03/2012, through 01/06/2012 for use in the course "Proteins and Molecular Mechanisms" taught by Robert B. Rose at the North Carolina State University, Raleigh, NC USA. This reservation includes Sandbox Reserved 451 through Sandbox Reserved 500.

To get started: Click the edit this page tab at the top. Save the page after each step, then edit it again. Click the 3D button (when editing, above the wikitext box) to insert Jmol. show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page. Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc. More help: Help:Editing For more help, look at this link: http://www.proteopedia.org/wiki/index.php/Help:Getting_Started_in_Proteopedia Cholix Toxin named also CT, and CTX is a bacterial protein-toxin secreted by Vibrio cholerea which uses ADP-ribosyltransferase enzymes to modify target proteins located in human cells. The mono-ADP-ribosyltransferase toxins are bacterial virulence factors that are believed to be a factor in many disease states in animals plants as well even humans. For a list of various and other similar toxins see Toxins. spinqualitylabelsall models X-Ray Diffraction image at 2.1Å of Cholix Toxin from Vibrio Cholerae Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Cholix Toxin from Vibrio Cholerae Cholix Toxin from Vibrio Cholerae The crystal structure of the purified form of Cholix Toxin or CT was determined in 1995. [3] It is an oligomeric bacterial protein found to be made up of six individual one single α-subunit and 5 individual β- subunits.The α-subunit makes up what is known as the enzymatic portion of the protein while the 5 copies of the β-subunit are responsible for the binding to the ligand receptor. The toxin binds highly specifically and tightly to a GM1 gangliosides on the surface of the host's cells. In this X-Ray Diffraction image we can see the site, which in this case has been complexed with an allosteric inhibitor (red and yellow space filling atoms). Recent studies have indicated several amino acid located proximally to the active site which are critical for enzymatic activity. Specifically, site directed mutagenesis indicated that when altered, the mutation results in a termination of the proteins toxicity, rendering it essentially harmless. Toxin MechanismToxin Mechanism Once secreted, the B subunit will bind to GM1 gangliosides on the surface. After binding takes place, the whole complex is engulfed by the cell and a portion known as the CTA1 chain is detached after reduction of a disulfide bridge. The new endosome is moved to the Golgi, where it is recognized by the endoplasmic reticulum, unfolded and delivered to the membrane, where the Endoplasmic Reticulum-oxidase - "Ero1" triggers the release of the excised A1 protein (through Oxidation) of protein disulfide isomerase complex. As A1 moves from the ER into the cytoplasm it refolds and avoids further reduction.[1] The A1 fragment catalyses ADP ribosylation from NAD to the regulatory component (G-protein) of adenylate cyclase, two main components in an important signal transduction pathway. The newly formed A1-Gαs complex is then unable to hydrolyse properly leaving the GTP bound to the Gαs subunit, which results in the transducer being continually activated. Increased adenylate cyclase activity increases cyclic AMP (cAMP concentration increases more than 100 times normal concentrations) synthesis. This can cause rapid fluid loss from the intestines, up to 2 liters per hour, leading to severe dehydration and diarrhea. Uses & Potential BenefitsUses & Potential Benefits While measures of treating someone with CX intoxication generally involves carefully replenishing electrolytes and other vital fluids there have been plenty of tests conducted that show that the toxin can be directly inhibited on the molecular level as well. The catalytic subunit of the CX protein has shown to bind, with high affinity a molecule known as PJ34- as well as other structurally conserved, fused-hydrocarbon ring inhibitors. Essentially, the PJ34 replaces what would target protein in the epithelial cell of a human host and prevent the ill effects of intoxication...in theory. spinqualitylabelsall models X-Ray Diffraction image at 2.1Å of catalytic fragment with PJ34 inhibitor bound. Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image An aspiration for research being done on the Cholera Toxin coincides with a current "hot topic" within the science community and society around the world: Stem Cell Research. There have been some recent findings indicating that the protein may be capable of interacting - regulation on the genetic level - some key factors in Neural Stem Cell (NSC) regeneration and differentiation. Known as Tie2, a membrane receptor, and Hes3 a transcription factor, these two indicators have been shown to directly interact with the Cholix Toxin. Moreover, there are even some implications that the protein, when combined with specific medium, boosted Stem Cell culture growth.[5] Thus, we see that apart from its potential to cause human illness, CX also poses the potential to offer a solution to cancer and other related diseases.