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botA

Gene
botA
Protein
Botulinum neurotoxin type A2
Organism
Clostridium botulinum (strain Kyoto / Type A2)
Length
1296 amino acids
Function
Botulinum neurotoxin A2 heavy chain: 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. It simultaneously recognizes 2 coreceptors; polysialated gangliosides and the receptor protein SV2 in close proximity on host synaptic vesicles (PubMed:28252640, PubMed:29649119). 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 to protect toxin prior to translocation (By similarity). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (By similarity).
Similarity
Belongs to the peptidase M27 family.
Mass
149.411 kDa
Sequence
MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHDVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAEHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDVASTLNKAKSIIGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVNFFKVINRKTYLNFDKAVFRINIVPDENYTIKDGFNLKGANLSTNFNGQNTEINSRNFTRLKNFTGLFEFYKLLCVRGIIPFKTKSLDEGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLDKVEEITADTNIEAAEENISLDLIQQYYLTFDFDNEPENISIENLSSDIIGQLEPMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGDSRIILTNSAEEALLKPNVAYTFFSSKYVKKINKAVEAFMFLNWAEELVYDFTDETNEVTTMDKIADITIIVPYIGPALNIGNMLSKGEFVEAIIFTGVVAMLEFIPEYALPVFGTFAIVSYIANKVLTVQTINNALSKRNEKWDEVYKYTVTNWLAKVNTQIDLIREKMKKALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINSAMININKFLDQCSVSYLMNSMIPYAVKRLKDFDASVRDVLLKYIYDNRGTLVLQVDRLKDEVNNTLSADIPFQLSKYVDNKKLLSTFTEYIKNIVNTSILSIVYKKDDLIDLSRYGAKINIGDRVYYDSIDKNQIKLINLESSTIEVILKNAIVYNSMYENFSTSFWIKIPKYFSKINLNNEYTIINCIENNSGWKVSLNYGEIIWTLQDNKQNIQRVVFKYSQMVNISDYINRWIFVTITNNRLTKSKIYINGRLIDQKPISNLGNIHASNKIMFKLDGCRDPRRYIMIKYFNLFDKELNEKEIKDLYDSQSNSGILKDFWGNYLQYDKPYYMLNLFDPNKYVDVNNIGIRGYMYLKGPRGSVVTTNIYLNSTLYEGTKFIIKKYASGNEDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKDDQGIRNKCKMNLQDNNGNDIGFIGFHLYDNIAKLVASNWYNRQVGKASRTFGCSWEFIPVDDGWGESSL

Gene
botA
Protein
Botulinum neurotoxin type A
Organism
Clostridium botulinum (strain Hall / ATCC 3502 / NCTC 13319 / Type A)
Length
1296 amino acids
Function
Botulinum neurotoxin A heavy chain: 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) (PubMed:9783750, PubMed:17173035). The RBD is responsible for the adherence of the toxin to the cell surface. It simultaneously recognizes 2 coreceptors; polysialated gangliosides and synaptic vesicle glycoproteins SV2A, SV2B and SV2C in close proximity on host synaptic vesicles (By similarity). The RBD specifically recognizes the N-linked glycan on 'Asn-559' of SV2A, SV2B and SV2C (By similarity). Isolated HC binds to host synaptosomes, significantly decreases uptake and toxicity of whole BoNT/A (PubMed:19476346). Binds ganglioside GD1a in vitro (PubMed:21849494). 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 to protect toxin prior to translocation (PubMed:9783750). The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (By similarity).
Similarity
Belongs to the peptidase M27 family.
Mass
149.426 kDa
Sequence
MPFVNKQFNYKDPVNGVDIAYIKIPNAGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL

Gene
botA
Protein
Botulinum neurotoxin type A
Organism
Clostridium botulinum
Length
1296 amino acids
Function
Botulinum neurotoxin A heavy chain: Responsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of botulinum neurotoxin A 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) (PubMed:19096517). The RBD is responsible for binding to host epithelial cells and transcytosis across them; this uses different receptors than those on nerve cells (PubMed:21106906). RBD is also responsible for adherence of toxin to host nerve cell surface; HC alone prevents uptake of whole toxin by neural cells, and delays paralysis onset by 75% (PubMed:6694738, PubMed:10413679). Isolated RBD also delays paralysis onset (PubMed:21106906). The N-terminus of the RBD binds to phosphatidylinositol, which might play a role in membrane-binding (PubMed:19161982). Binds to host protein receptor synaptic vesicle glycoproteins SV2A, SV2B and SV2C via lumenal loop 4 (PubMed:16545378, PubMed:6370252, PubMed:27294781, PubMed:24240280, PubMed:19650874, PubMed:27313224). Binding can be inhibited by protein fragments from either the HC or SV2C (PubMed:24240280). Isolated HC significantly decreases uptake and toxicity of whole BoNT/A, but also interferes with uptake of BoNT/E and to a lesser extent BoNT/F (PubMed:19650874). The RBD recognizes the N-linked glycan on 'Asn-559' of SV2A, SV2B and SV2C; hydrogen-bonding occurs via 10 well-defined water molecules and stacking of hydrophobic residues (PubMed:27294781). Binds one host GT1b ganglioside, which serves as a coreceptor (PubMed:14731268, PubMed:18704164, PubMed:27958736). Modeling shows the HC can bind both coreceptors (a ganglioside and SV2 protein) simultaneously at different sites (PubMed:24240280). Crystals of the RBD with a GT1b analog can be grown at pH 5.5, indicating the toxin-ganglioside complex could be stable within the endosome (PubMed:18704164). Isolated RBD binds NTNHA (a bacterial protein that protects toxin) with high affinity at pH 6.0 but not at pH 7.5 (PubMed:22363010). The N-terminal belt (residues 449-545) wraps around the perimeter of the LC, probably protecting Zn(2+) in the active site; it is not required for channel formation by the TD domain but may serve to prevent premature LC dissociation from the translocation channel and to protect toxin prior to translocation (PubMed:22158863, PubMed:17907800, PubMed:19351593). The isolated TD forms transmembrane channels of about 15 Angstroms in the absence of a pH gradient; LC translocation requires a pH and redox gradient (pH 5.0/oxidizing in the cis compartment, pH 7.0/reducing in the trans compartment), LC does not unfold unless the cis pH is 6.0 or less (PubMed:2446925, PubMed:17666397, PubMed:19096517). Pores are presumably made by 1-2 toxin molecules (PubMed:23471747). While interaction with the RBD modulates the pH threshold for membrane insertion, the RBD is not essential for toxin degradation of SNAP25 in neural cells (PubMed:19096517).
Similarity
Belongs to the peptidase M27 family.
Mass
149.454 kDa
Sequence
MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL