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Daggers of Death Daggers of Death Kettle Moraine SMART Team: Dams, Greg; Drachenberg, Disa; Goelz, Michael; Laux, Jacob; Kasper, David; Krause, Kris; Mayes, Melanie; Murray, Nathan; Swanson, Kaitlin; Tessman, Marsha Teachers: DeBoer, Karen; Nielsen, Peter; Plum, Stephen Mentor: Joseph Barbieri, Ph.D., Medical College of Wisconsin Abstract Molecular Structure of Botulism Serotype-A Clostridium botulinum, which causes Botulism, is a bacterium found in soil and in improperly processed foods. Botulism causes neuroparalytic diseases, where paralysis results in a part of the body because the nerves that supply it are diseased. Common symptoms of Botulism usually appear 12 to 36 hours after consumption and include a dry mouth, difficulty swallowing, slurred speech or difficulty speaking, muscle weakness, blurred or double vision, and drooping eyelids. Botulism works by blocking the release of neurotransmitters – chemicals which trigger neighboring nerves or activate muscle Catalytic cells – through the action of Clostridal Neurotoxins (CNTs) that break down soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, which are essential for fusion of the vesicle carrying the neurotransmitters Botulinum Neurotoxin serotype A with the cell membrane, thus releasing the neurotransmitters. If Receptor the neurotransmitters are not released, communication between Catalytic Binding Physical model of catalytic domain of nerve and muscle cells is halted, thus leading to paralysis. BoNT/A complexed with SNAP25 Botulinum Toxins (BoNTs) are composed of three domains: receptor, translocation, and catalytic. The receptor domain of Translocation BoNTs binds to receptors in the surface of neurons and enters PBD:3BTA (Daggers of Death) the neuron by receptor-mediated endocytosis. Once inside the neuron, the catalytic domain is translocated across the membrane of the vesicle by the translocation domain, into the cytosol, where the catalytic domain cleaves SNARE proteins. ® This blocks the release of neurotransmitters and leads to SNAP25’s Role in Vesicle Fusion How BOTOX cleaves SNAP25 Conclusion paralysis. SNAP25 is… In a normal neuron, SNAP25 •One of three SNARE proteins Botulism causes (limp) paralysis by blocking the fuses with the v-SNARE •Cleaved by BoNT/A at specific sites called exosites release of neurotransmitters. protein to allow the release of a •Defined as SyNaptosome-Associated Protein-25 kiloDaltons •It breaks down SNARE proteins responsible for neurotransmitter into the transmittance between nerve and muscle cells. Introduction synapse. The muscle cell can •There are seven serotypes of the botulism then respond to stimuli. neurotoxin: A-G •BoNT/A (the serotype used in BOTOX®) can be (Rossetto O, Montecucco, 2003) used to treat muscle spasms. This treatment results BoNT/A in normal control. Avian Botulism: •The SNAP25 complex in the neurotoxin breaks Ducks with flaccid paralysis SNAP25 the SNARE protein in the neck •When BoNT/A is mutated at two specific places it When the botulinum toxin is becomes ineffective as a cleaver of the SNARE (Leighton, 2000) a) SNAP25 is attached to a presynaptic membrane present, the light chain (the protein, even though it binds catalytic domain) cleaves Because the protein binds at exosites, the mutated b) Binding of BoNT/A with SNAP25 Blepharospasm: SNAP25 and SNAP 25 can no version could help scientists design specific inhibitors. (uncontrolled blinking) longer fuse with the v-SNARE c) Complex leading to cleavage of SNAP25 Before and After Botox protien; therefore, the Treatment neurotransmitters cannot be (Burns, 1986) released, and the muscle cell (Rossetto O, Montecucco,2003) cannot respond. •Clostridium botulinum, a bacteria found in the soil, produces a References toxin which targets neurons, causing paralysis. Therapeutic Uses Breidenbach, M, and Brunger, A. Substrate recognition strategy for botulinum neurotoxin •This toxin cleaves SNARE proteins, resulting in inhibited Botulinum Endotoxin (BOTOX®) has been approved by the Food serotype A. Nature 432(2004): 925-929. SNAP25-LC Schematic: Physical model of catalytic domain complexed with SNAP25 coordinates from PDB 1XTG vesicle fusion (the muscle can no longer communicate with the and Drug Administration to treat: Strabismus (lazy eye), In our model, there are Burns, CL, Gammon, JA, and Gemmill, MC. 1986. Ptosis associated with botulinum nerve). blepharospasm (uncontrolled blinking), cervical dystonia toxin treatment of strabismus and blepharospasm. Ophthalmology. 1986. 93(12):1621- mutations at two amino acid (involuntary muscle contractions in the neck), focal dystonia (the 7. Early description of the therapeutic use of BoNT •Botulism is the most toxic protein to humans! residues on the light chain: misfiring of neurons resulting in an undesirable muscle Gomersall, Gomersall. (2008). Syringes. Retrieved February 5, 2008, from •However, Botulism is also the most commonly used protein in E224Q and Y366F (orange). contractions), and severe primary axillary hyperhidrosis (excessive http://www.aic.cuhk.edu.hk/web8/Syringes.html medicine. Scientists did this in order to underarm sweating). BOTOX® is used for cosmetic treatments of Leighton, F.A. 2000. Signs of Disease in Affected Birds. In Type C Botulism in Birds. Retrieved February 5, 2008, from visualize the interactions wrinkles and frown lines. In the future, BOTOX® may be useful for •The Botulinum Neurotoxin has three domains: Receptor http://wildlife1.usask.ca/wildlife_health_topics/botulism/botulismc.php between BoNT/A and Snap25. treating tinnitus (ringing in the ears), urinary incontinence, and Binding, Catalytic, and Translocation. This mutated light chain bound, Rossetto O, Montecucco C. Chapter 2. How botulinum toxins work. In: Moore P, excessive scarring. Naumann M, editors. Handbook of Botulinum Toxin Treatment. 2nd Ed. Blackwell •There are seven serotypes of Botulism Neurotoxin (A-G). but did not cleave, SNAP25. Science 2003. Serotype A is used in BOTOX®. (Gomersall, 2008) A SMART Team project supported by the National Institutes of Health (NIH) – National Center for Research Resources Science Education Partnership Award (NCRR-SEPA).
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