Botulinum neurotoxin

From Proteopedia

Clostridium botulinum neurotoxin type A with cofactor Zn+2 (grey) (PDB code 3bta).

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1 Function
2 Disease
3 Relevance
4 Structural highlights
5 3D structures of botulinum neurotoxin

Function

Botulinum neurotoxin (CBN) is produced by the bacterium Clostridium botulinum. CBP contains a light (residues 1-440) and a heavy (residues 441-875) chains (LC and HC). CBP LC proteolyzes SNARE substrates (Synaptosomal-associated protein-25 or SNAP-25) which are essential for synaptic vesicle fusion and neurotransmitter release thus causing paralysis. CBP HC acts as a channel and as transmembrane chaperone enabling the passage of the LC into the cytosol. ^[1] The bacteria produces 8 neurotoxins which differ in their antigens.
See also Llama Antibody Inhibits Botulinum Neurotoxin.

Botulinum neurotoxin type A is the potent disease agent in botulism. See Clostridium botulinum neurotoxin serotype A light chain and Botulinum neurotoxin type A (Hebrew).
Botulinum neurotoxin type B is used for treatment of severe spasms in the neck muscles. See Clostridium Botulinum Neurotoxin Type B.
Botulinum neurotoxin type C induces apoptotic cell death in cerebellar neurons acting in birds, mammals and fish^[2].
Botulinum neurotoxin type D inhibits the release of TNF from monocytes.
Botulinum neurotoxin type DC binds and enters efficiently into neurons lacking complex gangliosides. It recognizes only sialic acid but no other gangliosides' moieties^[3].
Botulinum neurotoxin type E, F and G act on human proteins of the neuroexocytosis apparatus.
Botulinum neurotoxin type X cleaves both canonical and non-canonical vesicle-associated membrane proteins^[4].

Disease

CBP is the most lethal toxin known causing botulism.

Relevance

CBP type A is used by the cosmetics industry for smoothing wrinkles and is known commercially as Botox. It is used in the treatment of photophobia and Dry Eye^[5] and in treatment of individuals with certain pain conditions including migraine^[6]. In small quantities CBN can be used as muscle relaxant in cases of spasm and dystonia. CBP type E delivery to the hippocampus ia antiepileptogenic in models of epilepsy^[7].

Structural highlights

CBP contains a (LC, residues 1-440, in magenta) and a (HC, residues 441-1296, in cyan) chain. CBP HC contains two modules: the N-terminal (residues 441-875, in salmon) and the C-terminal (residues 876-1296, in yellow). . ^[8]

3D structures of botulinum neurotoxin

Botulinum neurotoxin 3D structures

References

↑ Montecucco C, Molgo J. Botulinal neurotoxins: revival of an old killer. Curr Opin Pharmacol. 2005 Jun;5(3):274-9. PMID:15907915 doi:http://dx.doi.org/10.1016/j.coph.2004.12.006
↑ Karalewitz AP, Fu Z, Baldwin MR, Kim JJ, Barbieri JT. Botulinum neurotoxin serotype C associates with dual ganglioside receptors to facilitate cell entry. J Biol Chem. 2012 Nov 23;287(48):40806-16. doi: 10.1074/jbc.M112.404244. Epub, 2012 Oct 1. PMID:23027864 doi:http://dx.doi.org/10.1074/jbc.M112.404244
↑ Zhang S, Berntsson RP, Tepp WH, Tao L, Johnson EA, Stenmark P, Dong M. Structural basis for the unique ganglioside and cell membrane recognition mechanism of botulinum neurotoxin DC. Nat Commun. 2017 Nov 21;8(1):1637. doi: 10.1038/s41467-017-01534-z. PMID:29158482 doi:http://dx.doi.org/10.1038/s41467-017-01534-z
↑ Zhang S, Masuyer G, Zhang J, Shen Y, Lundin D, Henriksson L, Miyashita SI, Martinez-Carranza M, Dong M, Stenmark P. Identification and characterization of a novel botulinum neurotoxin. Nat Commun. 2017 Aug 3;8:14130. doi: 10.1038/ncomms14130. PMID:28770820 doi:http://dx.doi.org/10.1038/ncomms14130
↑ Diel RJ, Kroeger ZA, Levitt RC, Sarantopoulos C, Sered H, Martinez-Barrizonte J, Galor A. Botulinum Toxin A for the Treatment of Photophobia and Dry Eye. Ophthalmology. 2018 Jan;125(1):139-140. doi: 10.1016/j.ophtha.2017.09.031. Epub, 2017 Oct 27. PMID:29110944 doi:http://dx.doi.org/10.1016/j.ophtha.2017.09.031
↑ Patil S, Willett O, Thompkins T, Hermann R, Ramanathan S, Cornett EM, Fox CJ, Kaye AD. Botulinum Toxin: Pharmacology and Therapeutic Roles in Pain States. Curr Pain Headache Rep. 2016 Mar;20(3):15. doi: 10.1007/s11916-016-0545-0. PMID:26879873 doi:http://dx.doi.org/10.1007/s11916-016-0545-0
↑ Costantin L, Bozzi Y, Richichi C, Viegi A, Antonucci F, Funicello M, Gobbi M, Mennini T, Rossetto O, Montecucco C, Maffei L, Vezzani A, Caleo M. Antiepileptic effects of botulinum neurotoxin E. J Neurosci. 2005 Feb 23;25(8):1943-51. doi: 10.1523/JNEUROSCI.4402-04.2005. PMID:15728834 doi:http://dx.doi.org/10.1523/JNEUROSCI.4402-04.2005
↑ Lacy DB, Tepp W, Cohen AC, DasGupta BR, Stevens RC. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat Struct Biol. 1998 Oct;5(10):898-902. PMID:9783750 doi:10.1038/2338