| 1.C.8 The Botulinum and Tetanus Toxin (BTT) Family
The BTT family consists of a variety of exoneurotoxins from Clostridium botulinum and C. tetani. These include botulinum neurotoxins A-G and tetanus neurotoxin. These proteins, sometimes called collectively, Clostridial Neurotoxins, resemble diptheria toxin (DT; TC #1.C.7.1.1) in that each of them is secreted as a single polypeptide chain and then cleaved to yield a disulfide-linked heterodimer of a light chain (L; residues 1-447 for botulinum toxin A (BTA)) and a heavy chain (H; residues 448-1295 for BTA). L has pharmacological activity as a proteolytic blocker of neurotransmitter release, cleaving synaptobrevin. The N- and C-termini of H mediate channel formation for transmembrane transport of BTA L-chain and receptor binding, respectively.
There are 10 a-helices and two putative transmembrane a-helical spanners (TMSs) (TH8 and TH9) in the translocation (T) domain of BTT family heavy chains [at positions 626-646 and 655-675 in BTA], and all members of the family exhibit a similar apparent topology. The N-terminal domain of H thus forms a protein translocation pathway. A T-domain fragment, consisting of TH8, TH9 and the interhelical TL5 loop, is sufficient for channel formation. Thus, the DT channel is formed by insertion of this helical hairpin into the membrane. The transport process is probably very similar to that mediated by diptheria toxin although DT does not show significant sequence similarity with BT or TT.
The transport reaction catalyzed by BTT family members is:
L-chain (out) Æ L-chain (in).
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| References: |
Binz, T., H. Kurazono, M. Wille, J. Frevert, K. Wernars and H. Niemann (1990). The complete sequence of botulinum neurotoxin type A and comparison with other clostridial neurotoxins. J. Biol. Chem. 265: 9153-9158.
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Binz, T., J. Blasi, S. Yamasaki, A. Baumeister, E. Link, T.C. Südhof, R. Jahn and H. Niemann (1994). Proteolysis of SNAP-25 by types E and A botulinal neurotoxins. J. Biol. Chem. 269: 1617-1620.
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Fairweather, N.F., V.A. Lyness, D.J. Pickard, G. Allen and R.O. Thomson (1986). Cloning, nucleotide sequencing, and expression of tetanus toxin fragment C in Escherichia coli. J. Bacteriol. 165: 21-27.
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Lacy, D.B. and R.C. Stevens (1998). Unraveling the structures and modes of action of bacterial toxins. Curr. Opin. Struct. Biol. 8: 778-784.
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Lacy, D.B. and R.C. Stevens (1999). Sequence homology and structural analysis of the clostridial neurotoxins. J. Mol. Biol. 291: 1091-1104.
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Lacy, D.B., W. Tepp, A.C. Cohen, B.R. DasGupta and R.C. Stevens (1998). Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nature Struct. Biol. 5: 898-902.
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Oh, K.J., H. Zhan, C. Cui, C. Altenbach, W.L. Hubbell and R.J. Collier (1999). Conformation of the diphtheria toxin T domain in membranes: a site-directed spin-labeling study of the TH8 helix and TL5 loop. Biochemistry 38: 10336-10343.
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Pellizzari, R., O. Rossetto, G. Schiavo and C. Montecucco (1999). Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses. Phil. Trans. R. Soc. Lond. B 354: 259-268.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.C.8.1.1 | Botulinum neurotoxin types A-G | Bacteria | Botulinum neurotoxin precursor, type A of Clostridium botulinum |
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| 1.C.8.1.2 | Tetanus neurotoxin | Bacteria | Tetanus neurotoxin precursor of Clostridium tetani |
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