Protein: BXA1_CLOBO
Sequence: MPFVNKQFNYKDPVNGVDIAYIKIPNVGQMQPVKAFKIHNKIWVIPERDTFTNPEEGDLNPPPEAKQVPVSYYDSTYLSTDNEKDNYLKGVTKLFERIYSTDLGRMLLTSIVRGIPFWGGSTIDTELKVIDTNCINVIQPDGSYRSEELNLVIIGPSADIIQFECKSFGHEVLNLTRNGYGSTQYIRFSPDFTFGFEESLEVDTNPLLGAGKFATDPAVTLAHELIHAGHRLYGIAINPNRVFKVNTNAYYEMSGLEVSFEELRTFGGHDAKFIDSLQENEFRLYYYNKFKDIASTLNKAKSIVGTTASLQYMKNVFKEKYLLSEDTSGKFSVDKLKFDKLYKMLTEIYTEDNFVKFFKVLNRKTYLNFDKAVFKINIVPKVNYTIYDGFNLRNTNLAANFNGQNTEINNMNFTKLKNFTGLFEFYKLLCVRGIITSKTKSLDKGYNKALNDLCIKVNNWDLFFSPSEDNFTNDLNKGEEITSDTNIEAAEENISLDLIQQYYLTFNFDNEPENISIENLSSDIIGQLELMPNIERFPNGKKYELDKYTMFHYLRAQEFEHGKSRIALTNSVNEALLNPSRVYTFFSSDYVKKVNKATEAAMFLGWVEQLVYDFTDETSEVSTTDKIADITIIIPYIGPALNIGNMLYKDDFVGALIFSGAVILLEFIPEIAIPVLGTFALVSYIANKVLTVQTIDNALSKRNEKWDEVYKYIVTNWLAKVNTQIDLIRKKMKEALENQAEATKAIINYQYNQYTEEEKNNINFNIDDLSSKLNESINKAMININKFLNQCSVSYLMNSMIPYGVKRLEDFDASLKDALLKYIYDNRGTLIGQVDRLKDKVNNTLSTDIPFQLSKYVDNQRLLSTFTEYIKNIINTSILNLRYESNHLIDLSRYASKINIGSKVNFDPIDKNQIQLFNLESSKIEVILKNAIVYNSMYENFSTSFWIRIPKYFNSISLNNEYTIINCMENNSGWKVSLNYGEIIWTLQDTQEIKQRVVFKYSQMINISDYINRWIFVTITNNRLNNSKIYINGRLIDQKPISNLGNIHASNNIMFKLDGCRDTHRYIWIKYFNLFDKELNEKEIKDLYDNQSNSGILKDFWGDYLQYDKPYYMLNLYDPNKYVDVNNVGIRGYMYLKGPRGSVMTTNIYLNSSLYRGTKFIIKKYASGNKDNIVRNNDRVYINVVVKNKEYRLATNASQAGVEKILSALEIPDVGNLSQVVVMKSKNDQGITNKCKMNLQDNNGNDIGFIGFHQFNNIAKLVASNWYNRQIERSSRTLGCSWEFIPVDDGWGERPL
What is the function of this protein?
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).
What are the official names of this protein?
Botulinum neurotoxin type A, BoNT/A, Bontoxilysin-A, BOTOX, Botulinum neurotoxin type A1.
What is the protein family that this protein belongs to?
Belongs to the peptidase M27 family.
What are the subcellular locations of this protein?
[Botulinum neurotoxin type A]: Secreted. Secreted, cell wall. Host synapse, host presynaptic cell membrane. Note=Whole toxin may be released from the bacteria during cell wall exfoliation (PubMed:7592120). There are estimated to be 150-500 toxin molecules per um(2) of non-myelinated mouse hemidiaphragm nerve membrane (PubMed:6694738). In mouse hemidiaphragm binds only to nerve terminals, and not to muscle, blood vessels, connective tissue Schwann cells or myelin, toxin can be internalized by this preparation (PubMed:6694738). SUBCELLULAR LOCATION: [Botulinum neurotoxin A light chain]: Secreted. Host cytoplasm, host cytosol. SUBCELLULAR LOCATION: [Botulinum neurotoxin A heavy chain]: Secreted. Host synapse, host presynaptic cell membrane. Host cytoplasmic vesicle, host secretory vesicle, host synaptic vesicle membrane; Multi-pass membrane protein. Note=Whole toxin may be released from the bacteria during cell wall exfoliation (PubMed:7592120). Colocalizes with its receptor SV2C (synaptic vesicle glycoprotein 2C) and VGAT (vesicular inhibitory amino acid transporter) in neurons (PubMed:24240280). In neurons HC colocalizes with synaptophysin or VAMP2 probably in synaptic vesicles, a portion also colocalizes with RAB5 and may be in synaptic vesicle protein sorting endosomes (PubMed:21632541, PubMed:21832053). Therefore there may be more than one uptake pathway at nerve terminals. Uptake of HC and whole toxin is slowed by dynamin inhibitors (PubMed:21832053). 1-2 molecules of HC are found in the host synaptic vesicle lumen, uptake and subsequent release of LC is very rapid (PubMed:21832053, PubMed:23471747).