3rsj

Structural highlights

Function

BXF_CLOBL Botulinum toxin causes flaccid paralysis by inhibiting neurotransmitter (acetylcholine) release from the presynaptic membranes of nerve terminals of the eukaryotic host skeletal and autonomic nervous system, with frequent heart or respiratory failure (PubMed:14423425). Precursor of botulinum neurotoxin F which may have 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins found in synaptic vesicles. Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them (PubMed:19476346, PubMed:19650874). Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway. When the pH of the toxin-containing endosome drops a structural rearrangement occurs so that the N-terminus of the HC forms pores that allows the light chain (LC) to translocate into the cytosol. Once in the cytosol the disulfide bond linking the 2 subunits is reduced and LC cleaves its target protein on synaptic vesicles, preventing their fusion with the cytoplasmic membrane and thus neurotransmitter release (By similarity). Requires complex gangliosides for full neurotoxicity (PubMed:19650874, PubMed:21483489). Electrical stimulation increases uptake of toxin, presumably by transiently exposing a receptor usually found in eukaryotic target synaptic vesicles (PubMed:19476346, PubMed:19650874). Blocks neurotransitter release by cleaving synaptobrevin-2/VAMP2 (PubMed:19476346). It is not clear whether a synaptic vesicle protein acts as its receptor; there is evidence for and against SV2 fulfilling this function (PubMed:19650874, PubMed:21483489, PubMed:19476346).[UniProtKB:P0DPI0]^{[1] [2] [3] [4]} Has protease activity (PubMed:19476346, PubMed:19543288). After translocation into the eukaryotic host cytosol, inhibits neurotransmitter release by acting as a zinc endopeptidase that catalyzes the hydrolysis of the '58-Gln-|-Lys-59' bond of synaptobrevin-2/VAMP2 and probably also the equivalent 'Gln-|-Lys' sites in VAMP1 and VAMP3 (PubMed:19476346, PubMed:19543288). Substrate specificity is conferred by multiple interactions of LC with substrate (PubMed:19543288).[UniProtKB:P30996]^{[5] [6]} Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into host cytosol. Composed of 3 subdomains; the translocation domain (TD), and N-terminus and C-terminus of the receptor-binding domain (RBD). The RBD is responsible for the adherence of the toxin to the cell surface (PubMed:19476346, PubMed:19650874). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site; it may also prevent premature LC dissociation from the translocation channel and protect toxin prior to translocation (By similarity). Isolated HC binds to host synaptosomes and neurons, significantly decreases uptake and toxicity of whole BoNT/F (PubMed:19476346, PubMed:19650874). Interferes with uptake of BoNT/E and to a lesser extent BoNT/C (PubMed:19650874). in vitro binds gangliosides GT1b, GD1b and GD1a (PubMed:19650874, PubMed:19476346, PubMed:21849494). Binds to synaptic vesicle glycoproteins SV2A, SV2B and SV2C which may serve as coreceptors with gangliosides (PubMed:19650874, PubMed:19476346). Interaction with SV2 proteins requires SV2 glycosylation (PubMed:19476346). However knockout SV2A/SV2B mice still cleave synaptobrevin, leaving the identification of its receptor unclear (PubMed:21483489).[UniProtKB:P0DPI0]^{[7] [8] [9]}

See Also

• Botulinum neurotoxin 3D structures

References

1. ↑ MOLLER V, SCHEIBEL I. Preliminary report on the isolation of an apparently new type of CI. botulinum. Acta Pathol Microbiol Scand. 1960;48:80. PMID:14423425 doi:10.1111/j.1699-0463.1960.tb04741.x
2. ↑ Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR. Glycosylated SV2 and Gangliosides as Dual Receptors for Botulinum Neurotoxin Serotype F. Biochemistry. 2009 Jun 23;48(24):5631-41. PMID:19476346 doi:10.1021/bi9002138
3. ↑ Rummel A, Häfner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, Binz T. Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J Neurochem. 2009 Sep;110(6):1942-54. PMID:19650874 doi:10.1111/j.1471-4159.2009.06298.x
4. ↑ Peng L, Tepp WH, Johnson EA, Dong M. Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS Pathog. 2011 Mar;7(3):e1002008. PMID:21483489 doi:10.1371/journal.ppat.1002008
5. ↑ Agarwal R, Schmidt JJ, Stafford RG, Swaminathan S. Mode of VAMP substrate recognition and inhibition of Clostridium botulinum neurotoxin F. Nat Struct Mol Biol. 2009 Jul;16(7):789-94. Epub 2009 Jun 21. PMID:19543288 doi:10.1038/nsmb.1626
6. ↑ Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR. Glycosylated SV2 and Gangliosides as Dual Receptors for Botulinum Neurotoxin Serotype F. Biochemistry. 2009 Jun 23;48(24):5631-41. PMID:19476346 doi:10.1021/bi9002138
7. ↑ Fu Z, Chen C, Barbieri JT, Kim JJ, Baldwin MR. Glycosylated SV2 and Gangliosides as Dual Receptors for Botulinum Neurotoxin Serotype F. Biochemistry. 2009 Jun 23;48(24):5631-41. PMID:19476346 doi:10.1021/bi9002138
8. ↑ Rummel A, Häfner K, Mahrhold S, Darashchonak N, Holt M, Jahn R, Beermann S, Karnath T, Bigalke H, Binz T. Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. J Neurochem. 2009 Sep;110(6):1942-54. PMID:19650874 doi:10.1111/j.1471-4159.2009.06298.x
9. ↑ Peng L, Tepp WH, Johnson EA, Dong M. Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides as receptors. PLoS Pathog. 2011 Mar;7(3):e1002008. PMID:21483489 doi:10.1371/journal.ppat.1002008