UniProtKB - P18640 (BXC_CBCP)
Botulinum neurotoxin type C
Functioni
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:16252491, PubMed:7901002, PubMed:8611567).
Is unique among characterized BoNTs in having 2 substrates, syntaxin (STX) and SNAP25 (PubMed:7901002, PubMed:7737992, PubMed:8611567, PubMed:9886085, PubMed:17718519).
Precursor of botulinum neurotoxin C which unlike most BoNTs seems not to have a proteinaceous coreceptor, and instead recognizes 2 different complex polysialylated gangliosides found on neural tissue probably found in synaptic vesicles (PubMed:21483489, PubMed:23027864).
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 heavy chain (HC) forms pores that allows the light chain (LC) to translocate into the cytosol (By similarity).
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).
In vitro the whole toxin only has protease activity after reduction (PubMed:8611567).
Electrical stimulation increases uptake of toxin, presumably by transiently exposing a receptor usually found in eukaryotic target synaptic vesicles (PubMed:19650874).
Forms ion-conducting channels at around pH 6.1 (PubMed:2424493).
Requires complex eukaryotic host polysialogangliosides for full neurotoxicity (PubMed:19650874, PubMed:21483489).
Synaptic vesicle glycoproteins (SV2) do not seem to act as its receptor (PubMed:21483489).
By similarity2 Publications8 PublicationsHas proteolytic activity. After translocation into the eukaryotic host cytosol, inhibits neurotransmitter release by acting as a zinc endopeptidase that cleaves syntaxin-1A/STX1A and syntaxin-1B/STX1B (PubMed:7901002, PubMed:7737992, PubMed:8611567).
Cleaves the '253-Arg-|-Ala-254' bond of STX1 and the '252-Arg-|-Ala-253' bond of STX2; also acts on syntaxin 3 (STX3) but not 4 (STX4) (PubMed:7737992).
Cleaves the '198-Arg-|-Ala-199' bond of SNAP25 (PubMed:8611567, PubMed:9886085, PubMed:17718519).
Recognizes the '93-Asn--Met-202' region of SNAP25 (PubMed:9886085).
5 PublicationsResponsible for host epithelial cell transcytosis, host nerve cell targeting and translocation of light chain (LC) into eukaryotic 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 eukaryotic target cell surface. It simultaneously recognizes 2 polysialated gangliosides coreceptors in close proximity on host synaptic vesicles (PubMed:23027864, PubMed:21542861).
The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn2+ in the active site; it may also prevent premature LC dissociation from the translocation channel and protect toxin prior to translocation (By similarity).
The TD inserts into synaptic vesicle membrane to allow translocation into the host cytosol (Probable). The C-terminal half of the HC (residues 864-1291) binds neurons in a dose-dependent manner (PubMed:20731382).
The C-terminal half of the HC (residues 863-1291) binds eukaryotic host gangliosides in the order GD1b > GT1b > GD1a > GM1a (PubMed:16115873, PubMed:20731382, PubMed:23027864, PubMed:19650874).
Has 2 ganglioside binding sites; Sia-1 prefers a sia7 sialic acid and sugars within the ganglioside (GD1b > GT1b), whereas GBP2 recognizes a sia5 sialic acid (GT1b and GD1a) (PubMed:23027864, PubMed:21542861).
Both sites are required for HC to enter neurons, acting via different gangliosides (PubMed:23027864).
This suggests that 2 gangliosides serve as toxin receptors (PubMed:16115873, PubMed:20731382, PubMed:21542861, PubMed:23027864).
Synaptic activity (depolarization with K+) increases uptake by neurons (PubMed:23027864).
Treatment of synaptosomes with proteinase K does not reduce HC binding, suggesting there is no protein receptor or it is protected from extracellular proteases (PubMed:16115873).
Decreases uptake and toxicity of whole BoNT/A, but also interferes with uptake of BoNT/E and BoNT/F (PubMed:19650874).
HC also binds phosphoinositides, which might play a role in membrane-binding (PubMed:22120109).
By similarity1 Publication6 PublicationsMiscellaneous
Catalytic activityi
- Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on small molecule substrates.3 Publications EC:3.4.24.69
Cofactori
Activity regulationi
Kineticsi
- KM=18.6 µM for purified SNAP25 with isolated botulinum neurotoxin C light chain1 Publication
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Metal bindingi | 229 | Zinc; via tele nitrogen; catalyticPROSITE-ProRule annotationCombined sources1 Publication | 1 | |
Active sitei | 230 | PROSITE-ProRule annotation | 1 | |
Metal bindingi | 233 | Zinc; via tele nitrogen; catalyticPROSITE-ProRule annotationCombined sources1 Publication | 1 | |
Metal bindingi | 269 | Zinc; catalyticCombined sources1 Publication | 1 | |
Binding sitei | 1119 | Ganglioside GD1a; GBP2 binding site1 Publication | 1 | |
Binding sitei | 1146 | Ganglioside GD1b; Sia-1 binding siteCombined sources1 Publication | 1 | |
Binding sitei | 1281 | Ganglioside GD1a; GBP2 binding site1 Publication | 1 |
GO - Molecular functioni
- ganglioside binding Source: UniProtKB
- metalloendopeptidase activity Source: UniProtKB-EC
- protein transmembrane transporter activity Source: InterPro
- toxin activity Source: UniProtKB
- zinc ion binding Source: UniProtKB
GO - Biological processi
- membrane protein proteolysis Source: CACAO
- negative regulation of calcium ion-dependent exocytosis Source: CACAO
- negative regulation of neurotransmitter secretion Source: UniProtKB
Keywordsi
Molecular function | Hydrolase, Metalloprotease, Neurotoxin, Protease, Toxin |
Biological process | Virulence |
Ligand | Lipid-binding, Metal-binding, Zinc |
Enzyme and pathway databases
BRENDAi | 3.4.24.69, 1462 |
Reactomei | R-HSA-5250971, Toxicity of botulinum toxin type C (botC) |
Protein family/group databases
UniLectini | P18640 |
Names & Taxonomyi
Protein namesi | Recommended name: Botulinum neurotoxin type CShort name: BoNT/C Alternative name(s): Bontoxilysin-C1 Short name: BoNT/C11 Publication Botulinum neurotoxin type C1 Cleaved into the following 2 chains: |
Organismi | Clostridium botulinum C phage (Clostridium botulinum C bacteriophage) |
Taxonomic identifieri | 12336 [NCBI] |
Taxonomic lineagei | Viruses › Duplodnaviria › Heunggongvirae › Uroviricota › Caudoviricetes › Caudovirales › Siphoviridae › |
Virus hosti | Clostridium botulinum C [TaxID: 36828] |
Subcellular locationi
- Secreted 1 Publication
- Secreted 2 Publications Note: Upon incubation with cultured neurons the HC is detected in a synaptophysin-positive intracellular compartment (probably host synaptic vesicles) (PubMed:23027864). It probably integrates into the eukaryotic host synaptic vesicle membrane (PubMed:2424493).1 Publication1 Publication
Keywords - Cellular componenti
SecretedPathology & Biotechi
Pharmaceutical usei
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 1119 | Y → A: Receptor-binding domain (RBD) no longer binds eukaryotic gangliosides GD1a or GM1a, reduced GT1b binding, GD1b binding unaffected. RBD fragment enters neurons but does not compartmentalize normally; uptake is not stimulated by K(+). 1 Publication | 1 | |
Mutagenesisi | 1126 | A → K: Receptor-binding domain (RBD) no longer binds eukaryotic gangliosides GM1a, GD1b, reduced binding of GD1a and GT1b. RBD fragment does not enter neurons; uptake is not stimulated by K(+). 1 Publication | 1 | |
Mutagenesisi | 1146 | Y → A: Whole toxin has dramatically reduced toxicity. 1 Publication | 1 | |
Mutagenesisi | 1179 | Y → S: Receptor-binding domain (RBD) has decreased binding to neurons. Greatly decreased binding to neurons; when associated with L-1258. Whole toxin has greatly decreased toxicity, even less toxic; when associated with L-1258. Decreased binding to mixed gangliosides, even less binding to mixed gangliosides; when associated with L-1258. 1 Publication | 1 | |
Mutagenesisi | 1193 | H → A: No effect on receptor-binding domain (RBD) binding to eukaryotic gangliosides. 1 Publication | 1 | |
Mutagenesisi | 1203 | L → F: Receptor-binding domain (RBD) has decreased binding to neurons. Whole toxin has greatly decreased toxicity. Decreased binding to mixed gangliosides. 1 Publication | 1 | |
Mutagenesisi | 1258 – 1259 | WY → AA: Whole toxin has greatly decreased toxicity. 1 Publication | 2 | |
Mutagenesisi | 1258 | W → A: Receptor-binding domain (RBD) has greatly reduced binding of ganglioside GD1b, no longer binds neurons. 1 Publication | 1 | |
Mutagenesisi | 1258 | W → L: Receptor-binding domain (RBD) has decreased binding to neurons (Ref.16). Greatly decreased binding to neurons; when associated with S-1179. Whole toxin has greatly decreased toxicity, even less toxic; when associated with S-1179. Decreased binding to mixed gangliosides, even less binding to mixed gangliosides; when associated with S-1179. 2 Publications | 1 | |
Mutagenesisi | 1281 | S → Y: Receptor-binding domain (RBD) has decreased binding to neurons. Whole toxin has decreased toxicity and decreased binding to mixed gangliosides. 1 Publication | 1 |
Chemistry databases
DrugBanki | DB13898, Equine Botulinum Neurotoxin C Immune FAB2 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Initiator methioninei | Removed1 Publication | |||
ChainiPRO_0000444905 | 2 – 1291 | Botulinum neurotoxin type CAdd BLAST | 1290 | |
ChainiPRO_0000029217 | 2 – 449 | Botulinum neurotoxin C light chainAdd BLAST | 448 | |
ChainiPRO_0000029218 | 450 – 1291 | Botulinum neurotoxin C heavy chainAdd BLAST | 842 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Disulfide bondi | 437 ↔ 453 | Interchain (between light and heavy chains)By similarityCurated |
Keywords - PTMi
Disulfide bondInteractioni
Subunit structurei
Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC) (PubMed:16252491). The LC has the proteolytic/pharmacological activity (PubMed:7901002, PubMed:7737992, PubMed:8611567). The N- and C-terminal of the HC mediate channel formation and toxin binding, respectively. Can also be purified in complex with a non-toxic component that is larger than the HC (PubMed:16252491, PubMed:7802661). The stoichiometry of the whole complex has been modeled as one BoNT/C, one NTNHA, three HA-70, six HA-33 and three HA-17 (By similarity).
By similarity5 PublicationsStructurei
Secondary structure
3D structure databases
SMRi | P18640 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P18640 |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 450 – 865 | Translocation domain (TD)By similarityAdd BLAST | 416 | |
Regioni | 490 – 541 | BeltBy similarityAdd BLAST | 52 | |
Regioni | 866 – 1093 | N-terminus of receptor binding domain (N-RBD)By similarityAdd BLAST | 228 | |
Regioni | 1094 – 1291 | C-terminus of receptor binding domain (C-RBD)By similarityAdd BLAST | 198 | |
Regioni | 1126 – 1129 | Ganglioside GD1b; Sia-1 binding siteCombined sources1 Publication | 4 | |
Regioni | 1247 – 1250 | Ganglioside GD1a; GBP2 binding site1 Publication | 4 | |
Regioni | 1269 – 1283 | Ganglioside-binding loop2 PublicationsAdd BLAST | 15 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 1256 – 1258 | Host ganglioside-binding motifBy similarity1 Publication | 3 |
Domaini
Sequence similaritiesi
Family and domain databases
Gene3Di | 1.20.1120.10, 1 hit |
InterProi | View protein in InterPro IPR000395, Bot/tetX_LC IPR036248, Clostridium_toxin_transloc IPR013320, ConA-like_dom_sf IPR011065, Kunitz_inhibitor_STI-like_sf IPR013104, Toxin_rcpt-bd_C IPR012928, Toxin_rcpt-bd_N IPR012500, Toxin_trans |
Pfami | View protein in Pfam PF01742, Peptidase_M27, 1 hit PF07951, Toxin_R_bind_C, 1 hit PF07953, Toxin_R_bind_N, 1 hit PF07952, Toxin_trans, 1 hit |
PRINTSi | PR00760, BONTOXILYSIN |
SUPFAMi | SSF49899, SSF49899, 1 hit SSF50386, SSF50386, 1 hit SSF58091, SSF58091, 1 hit |
PROSITEi | View protein in PROSITE PS00142, ZINC_PROTEASE, 1 hit |
i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
10 20 30 40 50
MPITINNFNY SDPVDNKNIL YLDTHLNTLA NEPEKAFRIT GNIWVIPDRF
60 70 80 90 100
SRNSNPNLNK PPRVTSPKSG YYDPNYLSTD SDKDTFLKEI IKLFKRINSR
110 120 130 140 150
EIGEELIYRL STDIPFPGNN NTPINTFDFD VDFNSVDVKT RQGNNWVKTG
160 170 180 190 200
SINPSVIITG PRENIIDPET STFKLTNNTF AAQEGFGALS IISISPRFML
210 220 230 240 250
TYSNATNDVG EGRFSKSEFC MDPILILMHE LNHAMHNLYG IAIPNDQTIS
260 270 280 290 300
SVTSNIFYSQ YNVKLEYAEI YAFGGPTIDL IPKSARKYFE EKALDYYRSI
310 320 330 340 350
AKRLNSITTA NPSSFNKYIG EYKQKLIRKY RFVVESSGEV TVNRNKFVEL
360 370 380 390 400
YNELTQIFTE FNYAKIYNVQ NRKIYLSNVY TPVTANILDD NVYDIQNGFN
410 420 430 440 450
IPKSNLNVLF MGQNLSRNPA LRKVNPENML YLFTKFCHKA IDGRSLYNKT
460 470 480 490 500
LDCRELLVKN TDLPFIGDIS DVKTDIFLRK DINEETEVIY YPDNVSVDQV
510 520 530 540 550
ILSKNTSEHG QLDLLYPSID SESEILPGEN QVFYDNRTQN VDYLNSYYYL
560 570 580 590 600
ESQKLSDNVE DFTFTRSIEE ALDNSAKVYT YFPTLANKVN AGVQGGLFLM
610 620 630 640 650
WANDVVEDFT TNILRKDTLD KISDVSAIIP YIGPALNISN SVRRGNFTEA
660 670 680 690 700
FAVTGVTILL EAFPEFTIPA LGAFVIYSKV QERNEIIKTI DNCLEQRIKR
710 720 730 740 750
WKDSYEWMMG TWLSRIITQF NNISYQMYDS LNYQAGAIKA KIDLEYKKYS
760 770 780 790 800
GSDKENIKSQ VENLKNSLDV KISEAMNNIN KFIRECSVTY LFKNMLPKVI
810 820 830 840 850
DELNEFDRNT KAKLINLIDS HNIILVGEVD KLKAKVNNSF QNTIPFNIFS
860 870 880 890 900
YTNNSLLKDI INEYFNNIND SKILSLQNRK NTLVDTSGYN AEVSEEGDVQ
910 920 930 940 950
LNPIFPFDFK LGSSGEDRGK VIVTQNENIV YNSMYESFSI SFWIRINKWV
960 970 980 990 1000
SNLPGYTIID SVKNNSGWSI GIISNFLVFT LKQNEDSEQS INFSYDISNN
1010 1020 1030 1040 1050
APGYNKWFFV TVTNNMMGNM KIYINGKLID TIKVKELTGI NFSKTITFEI
1060 1070 1080 1090 1100
NKIPDTGLIT SDSDNINMWI RDFYIFAKEL DGKDINILFN SLQYTNVVKD
1110 1120 1130 1140 1150
YWGNDLRYNK EYYMVNIDYL NRYMYANSRQ IVFNTRRNNN DFNEGYKIII
1160 1170 1180 1190 1200
KRIRGNTNDT RVRGGDILYF DMTINNKAYN LFMKNETMYA DNHSTEDIYA
1210 1220 1230 1240 1250
IGLREQTKDI NDNIIFQIQP MNNTYYYASQ IFKSNFNGEN ISGICSIGTY
1260 1270 1280 1290
RFRLGGDWYR HNYLVPTVKQ GNYASLLEST STHWGFVPVS E
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 85 | T → P in CAA37780 (PubMed:2204031). | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X66433 Genomic DNA Translation: CAA47060.1 X72793 Genomic DNA Translation: CAA51313.1 X53751 Genomic DNA Translation: CAA37780.1 D90210 Genomic DNA Translation: BAA14235.1 X62389 Genomic DNA Translation: CAA44263.1 AB200358 Genomic DNA Translation: BAD90566.1 |
RefSeqi | YP_398516.1, NC_007581.1 |
Genome annotation databases
GeneIDi | 3772941 |
KEGGi | vg:3772941 |
Similar proteinsi
Cross-referencesi
Web resourcesi
BotDB - A Database Resource for Clostridial Neurotoxins |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X66433 Genomic DNA Translation: CAA47060.1 X72793 Genomic DNA Translation: CAA51313.1 X53751 Genomic DNA Translation: CAA37780.1 D90210 Genomic DNA Translation: BAA14235.1 X62389 Genomic DNA Translation: CAA44263.1 AB200358 Genomic DNA Translation: BAD90566.1 |
RefSeqi | YP_398516.1, NC_007581.1 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2QN0 | X-ray | 1.75 | A | 1-427 | [»] | |
3DEB | X-ray | 1.95 | A | 1-430 | [»] | |
3N7K | X-ray | 2.50 | A/B | 866-1291 | [»] | |
3R4S | X-ray | 2.15 | A/B | 867-1291 | [»] | |
3R4U | X-ray | 2.20 | A/B | 867-1291 | [»] | |
SMRi | P18640 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Chemistry databases
DrugBanki | DB13898, Equine Botulinum Neurotoxin C Immune FAB2 |
Protein family/group databases
UniLectini | P18640 |
Genome annotation databases
GeneIDi | 3772941 |
KEGGi | vg:3772941 |
Enzyme and pathway databases
BRENDAi | 3.4.24.69, 1462 |
Reactomei | R-HSA-5250971, Toxicity of botulinum toxin type C (botC) |
Miscellaneous databases
EvolutionaryTracei | P18640 |
Family and domain databases
Gene3Di | 1.20.1120.10, 1 hit |
InterProi | View protein in InterPro IPR000395, Bot/tetX_LC IPR036248, Clostridium_toxin_transloc IPR013320, ConA-like_dom_sf IPR011065, Kunitz_inhibitor_STI-like_sf IPR013104, Toxin_rcpt-bd_C IPR012928, Toxin_rcpt-bd_N IPR012500, Toxin_trans |
Pfami | View protein in Pfam PF01742, Peptidase_M27, 1 hit PF07951, Toxin_R_bind_C, 1 hit PF07953, Toxin_R_bind_N, 1 hit PF07952, Toxin_trans, 1 hit |
PRINTSi | PR00760, BONTOXILYSIN |
SUPFAMi | SSF49899, SSF49899, 1 hit SSF50386, SSF50386, 1 hit SSF58091, SSF58091, 1 hit |
PROSITEi | View protein in PROSITE PS00142, ZINC_PROTEASE, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | BXC_CBCP | |
Accessioni | P18640Primary (citable) accession number: P18640 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | November 1, 1990 |
Last sequence update: | July 18, 2018 | |
Last modified: | September 29, 2021 | |
This is version 172 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Viral Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
3D-structure, Direct protein sequencing, PharmaceuticalDocuments
- Peptidase families
Classification of peptidase families and list of entries - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families