Botulinum neurotoxin type A

CovInDB Protein

P0DPI0

Name

Botulinum neurotoxin type A

Encoding Gene

botA

Synonyms

• BoNT/A
• Bontoxilysin-A
• BOTOX
• Botulinum neurotoxin type A1
• LC
• HC

Taxonomy

Clostridium botulinum

Description

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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:15394302, PubMed:7578132). Precursor of botulinum neurotoxin A which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins of synaptic vesicles. Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them. 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 (PubMed:17666397, PubMed:19096517). 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. Toxin activity requires polysialylated gangliosides; GT1b supports activity better than GD1a (PubMed:12089155). Binds to host peripheral neuronal presynaptic membranes via the synaptic vesicle glycoproteins SV2A, SV2B and SV2C (PubMed:16543415). It binds directly to the largest lumenal (intravesicular) loop of SV2A, SV2B and SV2C that is transiently exposed outside of cells during exocytosis; gangliosides enhance binding (PubMed:16543415, PubMed:16545378, PubMed:18815274). Recognizes an N-linked glycan on SV2 proteins (PubMed:18815274, PubMed:27294781). May also use FGFR3 as a receptor (PubMed:23696738). Toxin uptake into neural cells requires stimulation (incubation with K⁺ to stimulate receptor exposure) to be internalized by receptor-mediated endocytosis (PubMed:16543415, PubMed:19650874, PubMed:21632541, PubMed:21832053). Subsequently the toxin colocalizes with its receptor in host cells (PubMed:16543415, PubMed:19650874). Toxin uptake can be blocked by the appropriate SV2 protein fragments in cell culture (PubMed:16543415).

Sequence

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MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL

Active Site

Feature Key	Position(s)	Description
Binding site	1117	Host ganglioside GT1b
Binding site	1203	Host ganglioside GT1b
Metal binding	223	Zinc; via tele nitrogen; catalytic
Active site	224	Proton acceptor
Metal binding	227	Zinc; via tele nitrogen; catalytic
Metal binding	262	Zinc; catalytic
Site	363	Transition state stabilizer
Site	366	Transition state stabilizer

Structure

Check covalent ligand-protein complexes.

PDB:  4KS6

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Reference

UniProt

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