A beautiful toxin
Ribbon model of botulinum toxin serotype A (1).
Ribbon model of botulinum toxin serotype A (1).
The botulinum neurotoxin blocks signal transduction from occuring in motor neurons. The toxin causes flaccid paralysis by cleaving SNARE proteins that function in synaptic vesicle exocytosis. The toxin is produced by numerous species of Clostridium, most notable Clostridium botulinum. The toxic protein is expressed as a single chain 150kDa protein, which is cleaved into dichain proteins and bound by a disulfide bond with AB structure function properties. The N-terminal A domain measures nearly 50 kDa and functions as zinc metalloprotease. The C-terminal or B domain is approximately 100 kDa and is composed of two functional domains, which are involved in receptor recognition and translocation of the A domain across the endosomal membrane. The N-terminal or A domain is also classified as the Light Chain. The LC’s function as a mettalloprotease attacks fusion proteins (SNAP-25, syntaxin or synaptobrevin) at the neuromuscular junction, preventing vesicles from fusing with the membrane and releasing acetylcholine (2,3).
Acetylcholine is an imp
ortant neurotransmitter, which when bound to acetylcholine receptors on skeletal muscles, opens ligand gated sodium channels in the cell membrane. The Sodium ions enter the muscle cell and stimulate muscle contraction. Therefore, the cleavage of fusion proteins by the botulinum toxin inhibits the vesicles from binding to the acetylcholine receptors causing flaccid paralysis.
Fig. A. Model of binding of type B botulinum neurotoxin via both Syt-II and ganglioside receptors at the presynaptic membrane. The cytoplasm domain of synaptotagmin is presented as 2 C2 domains (light pink) bound with calcium ions (yellow spheres), modeled by 1TJX and 1DQV (4).*
Fig. B. Overview of type A1 botulinum neurotoxin (yellow) in complex with the CR1 antibody (antibody heavy and light chains in magenta and green, respectively)(5).*
**Above descriptions were taken from The Stevens Laboratory at The Scripps Research Institute, La Jolla, CA (6).
1. 3D ribbon model of botulinum neurotoxin serotype A (botox) from PDB 3BTA. Ref.: Lacy, D.B., Tepp, W., Cohen, A.C., DasGupta, B.R., Stevens, R.C. (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat.Struct.Biol. 5: 898-902
2. Foran PG, Mohammed N, Lisk GO, et al. (2003). "Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A. Basis for distinct durations of inhibition of exocytosis in central neurons". J. Biol. Chem. 278 (2): 1363–71.
3. Kukreja R, Singh BR (2009). "Botulinum Neurotoxins: Structure and Mechanism of Action". Microbial Toxins: Current Research and Future Trends. Caister Academic Press
4. Reprinted from Chai, Q., Arndt, J.W., Dong, M., Tepp, W.H., Johnson, E.A., Chapman, E.R., Stevens, R.C. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444:1096, 2006.
5.Reprinted from Garcia-Rodriguez, C., Levy, R., Arndt, J.W., Forsyth, C.M., Razai, A., Lou, J., Geren, I., Stevens, R.C., Marks, J.D. Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nat. Biotechnol. 25:107, 2007.
6. http://stevens.scripps.edu/BoNT.html
