Tetanospasmin

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File:Diagram of structure of tetanospasmin.png
Structure of tetanospasmin
Mechanism of action of tetanospasmin
Tetanus Toxin Heavy Chain C Fragment

Tetanus toxin is an extremely potent neurotoxin produced by the vegetative cell of Clostridium tetani[1] in anaerobic conditions, causing tetanus. It has no known function for clostridia in the soil environment where they are normally encountered. It is also called spasmogenic toxin, or TeNT. The LD50 of this toxin has been measured to be approximately 1 ng/kg, making it second only to Botulinum toxin as the deadliest toxin in the world.[2] However, these tests are conducted solely on mice which may react to the toxin differently from humans and other animals.

C. tetani also produces the exotoxin tetanolysin, a hemolysin, that causes destruction of tissues.[3]

Distribution

Tetanus toxin spreads through tissue spaces into the lymphatic and vascular systems. It enters the nervous system at the neuromuscular junctions and migrates through nerve trunks and into the central nervous system (CNS) by retrograde axonal transport by using dyneins.[4][5]

Structure

The tetanus toxin protein has a molecular weight of 150kDa. It is translated from the TetX gene as one protein which is subsequently cleaved into two parts: a 100kDa heavy or B-chain and a 50kDa light or A-chain. The chains are connected by a disulfide bond.

  • The B-chain binds to dissialogangliosides (GD2 and GD1b) on the neuronal membrane and contains a translocation domain which aids the movement of the protein across that membrane and into the neuron.
  • The A-chain, a zinc endopeptidase, attacks the vesicle-associated membrane protein (VAMP).

The TetX gene encoding this protein is located on the PE88 plasmid.[6] [7]

The sequence of this protein has been deposited in Uniprot with accession P04958

Several structures of the binding domain and the peptidase domain have been solved by X-ray crystallography and deposited in the PDB. A summary of these structures is available using the UniPDB application at PDBe, for example 1z7h or 3hmy.

Mechanism

The mechanism of TeNT action can be broken down and discussed in 6 different steps.

Transport
  1. Specific binding in the periphery neurons
  2. Retrograde axonal transport to the central nervous system (CNS) inhibitory interneurons
  3. Transcytosis from the axon into the inhibitory interneurons
Action
  1. Temperature and pH mediated translocation of the light chain into the cytosol
  2. Reduction of the disulphide bond between the light and heavy chain
  3. Cleavage of synaptobrevin

The first three steps outline the travel of tetanus from the peripheral nervous system to where it is taken up to the CNS and has its final effect. The last three steps document the changes necessary for the final mechanism of the neurotoxin.

Transport to the CNS inhibitory interneurons begins with The B-chain mediating the neurospecific binding of TeNT to the nerve terminal membrane. It binds to GT1b polysialogangliosides, similarly to the botulinum neurotoxin. It also binds another poorly characterized GPI anchored protein receptor more specific to TeNT.[8] [9] Both the ganglioside and the GPI anchored protein are located in lipid microdomains and both are requisite for specific TeNT binding.[9] Once it is bound the neurotoxin is then endocytosed into the nerve and begins to travel through the axon to the spinal neurons. The next step, transcytosis from the axon into the CNS inhibitory interneuron, is one of the least understood parts of TeNT action. At least two pathways are involved, one that relies on the recycling of synaptic vesicle 2 (SV2) system and one that does not.[10]

Once the vesicle is in the inhibitory interneuron its translocation is mediated by pH and temperature, specifically a low or acidic pH in the vesicle and standard physiological temperatures.[11] [12] Once the toxin has been translocated into the cytosol the disulfide bond is reduced, mainly by the NADPH-thioredoxin reductase-thioredoxin redox system and the light chain is free to cleave the Gln76-Phe77 bond of synaptobrevin.[13] Cleavage of synaptobrevin affects the stability of the SNARE core by restricting it from entering the low energy conformation which is the target for NSF binding.[14] Synaptobrevin is an integral V-SNARE necessary for vesicle fusion to membranes. The cleavage of synaptobrevin is the final target of TeNT and even in low doses the neurotoxin will inhibit neurotransmitter exocytosis in the inhibitory interneurons. The blockage of these neurotransmitters is what causes the physiological effects that accompany TeNT, specifically the blockage of the neurotransmitters GABA and glycine.

Tetanus toxin causes violent spastic paralysis by blocking the release of γ-aminobutyric acid (GABA). GABA is a neurotransmitter that inhibits motor neurons.[15]

The action of the A-chain stops the affected neurons from releasing the inhibitory neurotransmitters GABA and glycine, but also excitatory transmitters,[16] by degrading the protein synaptobrevin 2.[17] The consequence of this is dangerous overactivity in the muscles from the smallest stimulus—the failure of inhibition of motor reflexes by sensory stimulation. This causes generalized contractions of the agonist and antagonist musculature, termed a tetanic spasm.

Clinical significance

Tetanic spasms can occur in a distinctive form called opisthotonos and be sufficiently severe to fracture long bones. The shorter nerves are the first to be inhibited, which leads to the characteristic early symptoms in the face and jaw, risus sardonicus and lockjaw.

The toxin bind to the neurons is irreversible[4] and nerve function can only be returned by the growth of new terminals and synapses.

Immunity and vaccination

Due to its extreme potency, even a lethal dose of tetanospasmin may be insufficient to provoke an immune response. Naturally-acquired tetanus infections thus do not usually provide immunity to subsequent infections. Immunization (which is impermanent and must be repeated periodically) instead utilizes the less deadly toxoid derived from the toxin, as in the tetanus vaccine and some combination vaccines (such as DTP).

References

  1. ↑ "tetanospasmin" at Dorland's Medical Dictionary
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Tetanus toxin: primary structure, expression in E. coli, and homology with botulinum toxins. Eisel U. et al EMBO J. 5:2495-2502(1986) PubMed: 3536478
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Locations 19359-19360). Elsevier Health. Kindle Edition.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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