Sandbox Reserved 466: Difference between revisions

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The precursor polypeptide of the tetanus toxin is cleaved during post-translational modification into a heavy and light chains. These two chains remain linked by a disulfide bridge. The heavy chain is the C-terminal end of the protein and the light chain is the N-terminal end of the protein. If the two chains are separated, the toxin becomes non-toxic [PDB].

Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the specific neural receptors and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-binding domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Krishnamurthy et al., 2005].

Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the specific neural receptors and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-binding domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Krishnamurthy 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 zinc ion. 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 active site. 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 active site form a tetrahedral configuration around the catalytic zinc ion. This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the substrate. 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. The active site is illustrated in the figure below.

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== Mechanism of Action ==

Tetanus toxin binds to the neural cells through gangliosides and a second protein receptor. Once bound, they enter the cytosol via a vesicle membrane. Here, they attack and cleave the proteins that forms the synaptic vesicle fusion apparatus [Krishnamurthy et al., 2005].

Tetanus toxin binds to the neural cells through gangliosides and a second protein receptor. Once bound, they enter the cytosol via a vesicle membrane. Here, they attack and cleave the proteins that forms the synaptic vesicle fusion apparatus [Krishnamurthy et al., 2005]. The clostridial neurotoxins each have unique binding sites and substrate bond cleavage specificity. Tetanus toxin cleaves vesicle-associated membrane proteins.

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== Medical Implications or Possible Applications ==

Tetanus toxin is still a main concern to public health taking several hundred lives each year.

Tetanus toxin is still a main concern to public health taking several hundred lives each year. The most commonly used human vaccine is the chemically modified form of the tetanus neurotoxin.

Sandbox Reserved 466: Difference between revisions

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@@ Line 17: / Line 17: @@
 The precursor polypeptide of the tetanus toxin is cleaved during post-translational modification into a heavy and light chains. These two chains remain linked by a disulfide bridge. The heavy chain is the C-terminal end of the protein and the light chain is the N-terminal end of the protein. If the two chains are separated, the toxin becomes non-toxic [PDB].
-Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the specific neural receptors and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-binding domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Krishnamurthy et al., 2005].
+Tetanus toxin has three functional domains: binding, translocation, and catalytic. The heavy chain is responsible for binding the toxin to the specific neural receptors and translocating the catalytic light chain domain into the neural cytosol. The light chain is the zinc-binding domain containing a zinc-binding motif. This metalloprotease activity causes toxicity [Krishnamurthy 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 zinc ion. 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 active site. 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 active site form a tetrahedral configuration around the catalytic zinc ion. This interaction between the residues, water, and zinc are essential for the formation of nucleophilic water, which hydrolyzes the peptide bonds of the substrate. 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. The active site is illustrated in the figure below.
@@ Line 24: / Line 25: @@
 == Mechanism of Action ==
-Tetanus toxin binds to the neural cells through gangliosides and a second protein receptor. Once bound, they enter the cytosol via a vesicle membrane. Here, they attack and cleave the proteins that forms the synaptic vesicle fusion apparatus [Krishnamurthy et al., 2005].
+Tetanus toxin binds to the neural cells through gangliosides and a second protein receptor. Once bound, they enter the cytosol via a vesicle membrane. Here, they attack and cleave the proteins that forms the synaptic vesicle fusion apparatus [Krishnamurthy et al., 2005]. The clostridial neurotoxins each have unique binding sites and substrate bond cleavage specificity. Tetanus toxin cleaves vesicle-associated membrane proteins.
@@ Line 31: / Line 32: @@
 == Medical Implications or Possible Applications ==
-Tetanus toxin is still a main concern to public health taking several hundred lives each year.
+Tetanus toxin is still a main concern to public health taking several hundred lives each year. The most commonly used human vaccine is the chemically modified form of the tetanus neurotoxin.