Sandbox Reserved 466: Difference between revisions
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Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the presynaptic neuron membrane and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-dependent catalytic domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Rao et al., 2005]. The light chain forms a dimer with about 10% of the protein surface existing between the two monomers. Each monomer binds one <scene name='Sandbox_Reserved_466/Zinc_ion/1'>zinc ion</scene>. The active sites of the light chain tetanus toxin interact with the solvent region and are embedded inside a cavity centered around a zinc cation and the conserved zinc-dependent motif. Zinc directly coordinates with His232, His236, and Glu270 within the zinc-dependent <scene name='Sandbox_Reserved_466/Active_site/1'>active site</scene>. Water is another ligand that forms a hydrogen bond with Glu233. The formation of the nucleophilic water molecule and the three other amino acid residues in the [http://ars.els-cdn.com/content/image/1-s2.0-S0041010105000929-gr1.jpg tetanus toxin active site] form a tetrahedral configuration around the catalytic zinc ion | Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the presynaptic neuron membrane and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-dependent catalytic domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Rao et al., 2005]. The light chain forms a dimer with about 10% of the protein surface existing between the two monomers. Each monomer binds one <scene name='Sandbox_Reserved_466/Zinc_ion/1'>zinc ion</scene>. The active sites of the light chain tetanus toxin interact with the solvent region and are embedded inside a cavity centered around a zinc cation and the conserved zinc-dependent motif. Zinc directly coordinates with His232, His236, and Glu270 within the zinc-dependent <scene name='Sandbox_Reserved_466/Active_site/1'>active site</scene>. Water is another ligand that forms a hydrogen bond with Glu233. The formation of the nucleophilic water molecule and the three other amino acid residues in the [http://ars.els-cdn.com/content/image/1-s2.0-S0041010105000929-gr1.jpg tetanus toxin active site] form a tetrahedral configuration around the catalytic zinc ion. There is also a secondary layer important to the functionality of the active site. These residues are in the surrounding structure, approximately 10 Angstroms from the zinc ion, and they include Glu233, His239, Phe274, Arg371, and Tyr374. These residues reinforce the stability and conformation of the active site. | ||
== Mechanism of Action == | == Mechanism of Action == | ||
The tetanus toxin acts in the [http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana_1a.jpg synaptic cleft] of neuronal cells. Neurotransmitters are released from the presynaptic terminal of a neuron into the synaptic cleft and received by endocytosis by the postsynaptic terminal of the next neuron. Nerve terminals are filled with vesicles, which are specialized storage components that contain neurotransmitters, and are released from the terminal into the synaptic cleft by exocytosis. The surface of the postsynaptic terminal has many specialized receptors, which bind with specific vesicles. The neurotransmitters are then endocytized into the postsynaptic neuron for transmission of the synapse to facilitate a response to the nerve stimuli. | The tetanus toxin acts in the [http://thebrain.mcgill.ca/flash/i/i_01/i_01_m/i_01_m_ana/i_01_m_ana_1a.jpg synaptic cleft] of neuronal cells and prevents the release of neurotransmitters from the presynaptic neuron terminal [Link et al., 1992]. Neurotransmitters are released from the presynaptic terminal of a neuron into the synaptic cleft and received by endocytosis by the postsynaptic terminal of the next neuron. Nerve terminals are filled with vesicles, which are specialized storage components that contain neurotransmitters, and are released from the terminal into the synaptic cleft by exocytosis. The surface of the postsynaptic terminal has many specialized receptors, which bind with specific vesicles. The neurotransmitters are then endocytized into the postsynaptic neuron for transmission of the synapse to facilitate a response to the nerve stimuli. | ||
Tetanus toxin enters the bloodstream or directly binds with a neuronal cell after entering the body from a cut or abrasion. It binds to the neural cells through gangliosides and a protein receptor. Once bound, they enter the cytosol of the synaptic cleft of muscle fiber neurons via a vesicle membrane. Here, they attack and cleave the protein that forms the synaptic vesicle fusion apparatus, particularly [http://en.wikipedia.org/wiki/Synaptobrevin synaptobrevin] [Rao et al., 2005]. Synaptobrevin is a protein that forms [http://en.wikipedia.org/wiki/SNARE_proteins SNARE proteins], which mediate the fusion of synaptic vesicles to the presynaptic terminal. The clostridial neurotoxins each have unique binding sites and substrate cleavage specificity. Tetanus toxin cleaves vesicle-associated membrane proteins of synaptobrevin and inactivates it. The VAMP protein is cleaved at the peptide bond Gln76-Phe77 requiring a amino-terminal extension of 22 residues and a peptide of 33-97 residues in length [Rao et al., 2005]. | Tetanus toxin enters the bloodstream or directly binds with a neuronal cell after entering the body from a cut or abrasion. It binds to the neural cells through gangliosides and a protein receptor. Once bound, they enter the cytosol of the synaptic cleft of muscle fiber neurons via a vesicle membrane. Here, they attack and cleave the protein that forms the synaptic vesicle fusion apparatus, particularly [http://en.wikipedia.org/wiki/Synaptobrevin synaptobrevin] [Rao et al., 2005]. Synaptobrevin is a protein that forms [http://en.wikipedia.org/wiki/SNARE_proteins SNARE proteins], which mediate the fusion of synaptic vesicles to the presynaptic terminal. The clostridial neurotoxins each have unique binding sites and substrate cleavage specificity. Tetanus toxin cleaves vesicle-associated membrane proteins of synaptobrevin and inactivates it. The VAMP protein is cleaved at the peptide bond Gln76-Phe77 requiring a amino-terminal extension of 22 residues and a peptide of 33-97 residues in length [Rao et al., 2005]. | ||
This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the substrate. | |||
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Dasgupta, B. R. (1993). Botulinum and tetanus neurotoxins: Neurotransmission and biomedical aspects. New York: Plenum Press. | Dasgupta, B. R. (1993). Botulinum and tetanus neurotoxins: Neurotransmission and biomedical aspects. New York: Plenum Press. | ||
Link, E., Edelmann, L., Chou, J., & Binz, T. (1992). Tetanus toxin action: Inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochemical and Biophysical Research Communications, 189(2), 1017-1023. Retrieved from http://www.sciencedirect.com/science/article/pii/0006291X9292305H. | |||
Montecucco, C. (1995). Clostridial neurotoxins: The molecular pathogenesis of tetanus and botulism. Germany: Springer. | Montecucco, C. (1995). Clostridial neurotoxins: The molecular pathogenesis of tetanus and botulism. Germany: Springer. | ||
