UniProt functional annotation for P0DPI1



	UniProt functional annotation for P0DPI1

UniProt codes: P0DPI1, P10845.

Organism: Clostridium botulinum (strain Hall / ATCC 3502 / NCTC 13319 / Type A).

Taxonomy: Bacteria; Firmicutes; Clostridia; Eubacteriales; Clostridiaceae; Clostridium.

Function: [Botulinum neurotoxin type A]: 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:8103915). Precursor of botulinum neurotoxin A which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins of synaptic vesicles (By similarity). Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them (PubMed:19476346). Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway (By similarity). 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 (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). {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:19476346, ECO:0000269|PubMed:8103915}.

Function: [Botulinum neurotoxin A light chain]: Has proteolytic activity (PubMed:8103915, PubMed:8294407). In vitro the whole toxin is reduced to release LC (PubMed:8103915, PubMed:8294407). After translocation into the eukaryotic host cytosol, LC hydrolyzes the 197- Gln-|-Arg-198 bond in SNAP25, blocking neurotransmitter release (PubMed:8103915, PubMed:8294407). {ECO:0000269|PubMed:8103915, ECO:0000269|PubMed:8294407, ECO:0000305|PubMed:19476346}.

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). {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:19476346, ECO:0000269|PubMed:21849494, ECO:0000269|PubMed:9783750}.

Catalytic activity: Reaction=Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on small molecule substrates.; EC=3.4.24.69; Evidence={ECO:0000269|PubMed:8103915, ECO:0000269|PubMed:8294407};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:21434688, ECO:0000269|PubMed:9783750}; Note=Binds 1 zinc ion per subunit (PubMed:9783750, PubMed:17173035, PubMed:21434688). {ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:21434688, ECO:0000269|PubMed:9783750};

Activity regulation: SNAP25 proteolysis is inhibited by 1,10- phenanthroline and 2,2'-dipyridyl but not EDTA (PubMed:8103915). Inhibited by hydroxamate compounds with halogenated benzene-containing arms which directly bind the zinc ion (PubMed:21434688). {ECO:0000269|PubMed:21434688, ECO:0000269|PubMed:8103915}.

Subunit: Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC) (PubMed:9783750, PubMed:17173035). Interacts with host synaptic vesicle glycoproteins SV2A, SV2B and SV2C which serve as coreceptors (By similarity). Glycosylation of 'Asn-559' in SV2C probably contributes a 12-fold increase in affinity to this interaction (By similarity). Depolarization of target tissue with high levels of K(+) leads to greater levels of receptor exposure (PubMed:19476346). {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:19476346, ECO:0000269|PubMed:9783750}.

Subcellular location: [Botulinum neurotoxin A light chain]: Secreted {ECO:0000305|PubMed:9783750}. Host cytoplasm, host cytosol {ECO:0000305|PubMed:8103915, ECO:0000305|PubMed:8294407}.

Subcellular location: [Botulinum neurotoxin A heavy chain]: Secreted {ECO:0000305|PubMed:9783750}. Host cell junction, host synapse, host presynaptic cell membrane {ECO:0000269|PubMed:19476346}. Host cytoplasmic vesicle, host secretory vesicle, host synaptic vesicle membrane {ECO:0000305|PubMed:19476346}; Multi-pass membrane protein {ECO:0000305}.

Domain: [Botulinum neurotoxin A light chain]: Has protease activity (PubMed:8103915, PubMed:8294407). {ECO:0000269|PubMed:8103915, ECO:0000269|PubMed:8294407}.

Domain: [Botulinum neurotoxin A heavy chain]: Has 3 functional domains; the translocation domain (TD) and the receptor-binding domain (RBD) which is further subdivided into N- and C-terminal domains (N-RBD and C-RBD) (PubMed:17173035, PubMed:19476346). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site and may be a pseudosubstrate inhibitor which serves as an intramolecular chaperone for the LC prior to its translocation into the host cytosol (PubMed:9783750). The RBD binds transiently exposed coreceptors on the host presynaptic cell membrane (PubMed:19476346). {ECO:0000269|PubMed:17173035, ECO:0000269|PubMed:19476346, ECO:0000269|PubMed:9783750}.

Pharmaceutical: Available under the name Botox (onabotulinumtoxinA, Allergan), Dysport (abobotulinumtoxinA, Ipsen Biopharmaceuticals) and Xeomin (incobotulinumtoxinA, Merz Pharmaceuticals) for the treatment of strabismus and blepharospasm associated with dystonia and cervical dystonia. Used for the treatment of hemifacial spasm and a number of other neurological disorders characterized by abnormal muscle contraction. It is also used cosmetically to smooth facial wrinkles. {ECO:0000305|PubMed:28356439}.

Miscellaneous: There are seven antigenically distinct forms of botulinum neurotoxin: Types A, B, C, D, E, F, and G; new subtypes are quite frequent.

Miscellaneous: Botulism poisoning is usually food-borne, either by ingesting toxin or bacterial-contaminated food, or less frequently by inhalation poisoning. In both cases the neurotoxin binds to the apical surface of epithelial cells in the gut or airway. Toxin undergoes receptor-mediated endocytosis (using a different receptor than on target nerve cells), transcytosis across the epithelial cells and release into the general circulation. Once in the general circulation it binds to its target cells. {ECO:0000250|UniProtKB:P0DPI0}.

Miscellaneous: Types A, B and E are the most frequent cause of adult human foodborne botulism; type A is the most severe, while type E has the shortest incubation period (PubMed:1431246). {ECO:0000269|PubMed:1431246}.

Miscellaneous: Neurotoxin type A is released from bacteria in the two- chain form (PubMed:4030755). {ECO:0000269|PubMed:4030755}.

Miscellaneous: Neutralizing antibodies are used to treat botulism; in at least 2 cases they bind to HC. {ECO:0000269|PubMed:17173035}.

Similarity: Belongs to the peptidase M27 family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Clostridium botulinum (strain Hall / ATCC 3502 / NCTC 13319 / Type A).
Taxonomy:		Bacteria; Firmicutes; Clostridia; Eubacteriales; Clostridiaceae; Clostridium.



Function:		[Botulinum neurotoxin type A]: 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:8103915). Precursor of botulinum neurotoxin A which has 2 coreceptors; complex polysialylated gangliosides found on neural tissue and specific membrane-anchored proteins of synaptic vesicles (By similarity). Receptor proteins are exposed on host presynaptic cell membrane during neurotransmitter release, when the toxin heavy chain (HC) binds to them (PubMed:19476346). Upon synaptic vesicle recycling the toxin is taken up via the endocytic pathway (By similarity). 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 (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). {ECO:0000250\|UniProtKB:P0DPI0, ECO:0000269\|PubMed:19476346, ECO:0000269\|PubMed:8103915}.



Function:		[Botulinum neurotoxin A light chain]: Has proteolytic activity (PubMed:8103915, PubMed:8294407). In vitro the whole toxin is reduced to release LC (PubMed:8103915, PubMed:8294407). After translocation into the eukaryotic host cytosol, LC hydrolyzes the 197- Gln-\|-Arg-198 bond in SNAP25, blocking neurotransmitter release (PubMed:8103915, PubMed:8294407). {ECO:0000269\|PubMed:8103915, ECO:0000269\|PubMed:8294407, ECO:0000305\|PubMed:19476346}.



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). {ECO:0000250\|UniProtKB:P0DPI0, ECO:0000269\|PubMed:17173035, ECO:0000269\|PubMed:19476346, ECO:0000269\|PubMed:21849494, ECO:0000269\|PubMed:9783750}.


Catalytic activity:		Reaction=Limited hydrolysis of proteins of the neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on small molecule substrates.; EC=3.4.24.69; Evidence={ECO:0000269\|PubMed:8103915, ECO:0000269\|PubMed:8294407};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:17173035, ECO:0000269\|PubMed:21434688, ECO:0000269\|PubMed:9783750}; Note=Binds 1 zinc ion per subunit (PubMed:9783750, PubMed:17173035, PubMed:21434688). {ECO:0000269\|PubMed:17173035, ECO:0000269\|PubMed:21434688, ECO:0000269\|PubMed:9783750};
Activity regulation:		SNAP25 proteolysis is inhibited by 1,10- phenanthroline and 2,2'-dipyridyl but not EDTA (PubMed:8103915). Inhibited by hydroxamate compounds with halogenated benzene-containing arms which directly bind the zinc ion (PubMed:21434688). {ECO:0000269\|PubMed:21434688, ECO:0000269\|PubMed:8103915}.
Subunit:		Heterodimer; disulfide-linked heterodimer of a light chain (LC) and a heavy chain (HC) (PubMed:9783750, PubMed:17173035). Interacts with host synaptic vesicle glycoproteins SV2A, SV2B and SV2C which serve as coreceptors (By similarity). Glycosylation of 'Asn-559' in SV2C probably contributes a 12-fold increase in affinity to this interaction (By similarity). Depolarization of target tissue with high levels of K(+) leads to greater levels of receptor exposure (PubMed:19476346). {ECO:0000250\|UniProtKB:P0DPI0, ECO:0000269\|PubMed:17173035, ECO:0000269\|PubMed:19476346, ECO:0000269\|PubMed:9783750}.
Subcellular location:		[Botulinum neurotoxin A light chain]: Secreted {ECO:0000305\|PubMed:9783750}. Host cytoplasm, host cytosol {ECO:0000305\|PubMed:8103915, ECO:0000305\|PubMed:8294407}.
Subcellular location:		[Botulinum neurotoxin A heavy chain]: Secreted {ECO:0000305\|PubMed:9783750}. Host cell junction, host synapse, host presynaptic cell membrane {ECO:0000269\|PubMed:19476346}. Host cytoplasmic vesicle, host secretory vesicle, host synaptic vesicle membrane {ECO:0000305\|PubMed:19476346}; Multi-pass membrane protein {ECO:0000305}.
Domain:		[Botulinum neurotoxin A light chain]: Has protease activity (PubMed:8103915, PubMed:8294407). {ECO:0000269\|PubMed:8103915, ECO:0000269\|PubMed:8294407}.
Domain:		[Botulinum neurotoxin A heavy chain]: Has 3 functional domains; the translocation domain (TD) and the receptor-binding domain (RBD) which is further subdivided into N- and C-terminal domains (N-RBD and C-RBD) (PubMed:17173035, PubMed:19476346). The N-terminus of the TD wraps an extended belt around the perimeter of the LC, protecting Zn(2+) in the active site and may be a pseudosubstrate inhibitor which serves as an intramolecular chaperone for the LC prior to its translocation into the host cytosol (PubMed:9783750). The RBD binds transiently exposed coreceptors on the host presynaptic cell membrane (PubMed:19476346). {ECO:0000269\|PubMed:17173035, ECO:0000269\|PubMed:19476346, ECO:0000269\|PubMed:9783750}.
Pharmaceutical:		Available under the name Botox (onabotulinumtoxinA, Allergan), Dysport (abobotulinumtoxinA, Ipsen Biopharmaceuticals) and Xeomin (incobotulinumtoxinA, Merz Pharmaceuticals) for the treatment of strabismus and blepharospasm associated with dystonia and cervical dystonia. Used for the treatment of hemifacial spasm and a number of other neurological disorders characterized by abnormal muscle contraction. It is also used cosmetically to smooth facial wrinkles. {ECO:0000305\|PubMed:28356439}.
Miscellaneous:		There are seven antigenically distinct forms of botulinum neurotoxin: Types A, B, C, D, E, F, and G; new subtypes are quite frequent.
Miscellaneous:		Botulism poisoning is usually food-borne, either by ingesting toxin or bacterial-contaminated food, or less frequently by inhalation poisoning. In both cases the neurotoxin binds to the apical surface of epithelial cells in the gut or airway. Toxin undergoes receptor-mediated endocytosis (using a different receptor than on target nerve cells), transcytosis across the epithelial cells and release into the general circulation. Once in the general circulation it binds to its target cells. {ECO:0000250\|UniProtKB:P0DPI0}.
Miscellaneous:		Types A, B and E are the most frequent cause of adult human foodborne botulism; type A is the most severe, while type E has the shortest incubation period (PubMed:1431246). {ECO:0000269\|PubMed:1431246}.
Miscellaneous:		Neurotoxin type A is released from bacteria in the two- chain form (PubMed:4030755). {ECO:0000269\|PubMed:4030755}.
Miscellaneous:		Neutralizing antibodies are used to treat botulism; in at least 2 cases they bind to HC. {ECO:0000269\|PubMed:17173035}.
Similarity:		Belongs to the peptidase M27 family. {ECO:0000305}.