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Botulinum neurotoxin type A (BoNT/A) (EC 3.4.24.69) (Bontoxilysin-A) (BOTOX) [Cleaved into: Botulinum neurotoxin A light chain; Botulinum neurotoxin A heavy chain]

 BXA1_CLOBH              Reviewed;        1296 AA.
P0DPI1; A5HZZ9; A7G1U9; P01561; P10845; P18639;
18-JUL-2018, integrated into UniProtKB/Swiss-Prot.
18-JUL-2018, sequence version 1.
18-JUL-2018, entry version 1.
RecName: Full=Botulinum neurotoxin type A;
Short=BoNT/A;
AltName: Full=Bontoxilysin-A;
Short=BOTOX;
Contains:
RecName: Full=Botulinum neurotoxin A light chain;
Short=LC;
EC=3.4.24.69 {ECO:0000269|PubMed:8103915};
Contains:
RecName: Full=Botulinum neurotoxin A heavy chain;
Short=HC;
Flags: Precursor;
Name=botA {ECO:0000303|PubMed:17519437};
Synonyms=bna {ECO:0000303|PubMed:2669749};
OrderedLocusNames=CBO0806, CLC_0862;
Clostridium botulinum (strain Hall / ATCC 3502 / NCTC 13319 / Type A).
Bacteria; Firmicutes; Clostridia; Clostridiales; Clostridiaceae;
Clostridium.
NCBI_TaxID=441771;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
STRAIN=Hall / ATCC 3502 / NCTC 13319 / Type A;
PubMed=17519437; DOI=10.1101/gr.6282807;
Sebaihia M., Peck M.W., Minton N.P., Thomson N.R., Holden M.T.G.,
Mitchell W.J., Carter A.T., Bentley S.D., Mason D.R., Crossman L.,
Paul C.J., Ivens A., Wells-Bennik M.H.J., Davis I.J.,
Cerdeno-Tarraga A.M., Churcher C., Quail M.A., Chillingworth T.,
Feltwell T., Fraser A., Goodhead I., Hance Z., Jagels K., Larke N.,
Maddison M., Moule S., Mungall K., Norbertczak H., Rabbinowitsch E.,
Sanders M., Simmonds M., White B., Whithead S., Parkhill J.;
"Genome sequence of a proteolytic (Group I) Clostridium botulinum
strain Hall A and comparative analysis of the clostridial genomes.";
Genome Res. 17:1082-1092(2007).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
STRAIN=Hall / ATCC 3502 / NCTC 13319 / Type A;
PubMed=18060065; DOI=10.1371/journal.pone.0001271;
Smith T.J., Hill K.K., Foley B.T., Detter J.C., Munk A.C., Bruce D.C.,
Doggett N.A., Smith L.A., Marks J.D., Xie G., Brettin T.S.;
"Analysis of the neurotoxin complex genes in Clostridium botulinum A1-
A4 and B1 strains: BoNT/A3, /Ba4 and /B1 clusters are located within
plasmids.";
PLoS ONE 2:E1271-E1271(2007).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-35.
STRAIN=Hall / Type A;
PubMed=2669749; DOI=10.1016/0006-291X(89)90828-0;
Betley M.J., Somers E., Dasgupta B.R.;
"Characterization of botulinum type A neurotoxin gene: delineation of
the N-terminal encoding region.";
Biochem. Biophys. Res. Commun. 162:1388-1395(1989).
[4]
PROTEIN SEQUENCE OF 449-475 AND 873-896.
STRAIN=Hall / Type A;
PubMed=3178218; DOI=10.1016/0003-9861(88)90244-5;
Sathymoorthy V., Dasgupta B.R., Foley J., Niece R.L.;
"Botulinum neurotoxin type A: cleavage of the heavy chain into two
halves and their partial sequences.";
Arch. Biochem. Biophys. 266:142-151(1988).
[5]
PROTEIN SEQUENCE OF 867-880 AND 1148-1219.
STRAIN=Hall / Type A;
PubMed=8397793; DOI=10.1007/BF01028197;
Gimenez J.A., DasGupta B.R.;
"Botulinum type A neurotoxin digested with pepsin yields 132, 97, 72,
45, 42, and 18 kD fragments.";
J. Protein Chem. 12:351-363(1993).
[6]
RELEASED AS DICHAIN.
STRAIN=Hall / Type A;
PubMed=4030755;
Sathyamoorthy V., DasGupta B.R.;
"Separation, purification, partial characterization and comparison of
the heavy and light chains of botulinum neurotoxin types A, B, and
E.";
J. Biol. Chem. 260:10461-10466(1985).
[7]
HOST RANGE, AND EPIDEMIOLOGY.
PubMed=1431246;
Woodruff B.A., Griffin P.M., McCroskey L.M., Smart J.F.,
Wainwright R.B., Bryant R.G., Hutwagner L.C., Hatheway C.L.;
"Clinical and laboratory comparison of botulism from toxin types A, B,
and E in the United States, 1975-1988.";
J. Infect. Dis. 166:1281-1286(1992).
[8]
FUNCTION (BOTULINUM NEUROTOXIN TYPE A AND BOTULINUM NEUROTOXIN A LIGHT
CHAIN), IDENTIFICATION OF SUBSTRATE, CATALYTIC ACTIVITY, ENZYME
REGULATION, SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A LIGHT CHAIN),
AND MUTAGENESIS OF GLU-224.
STRAIN=Hall / Type A;
PubMed=8103915; DOI=10.1038/365160a0;
Blasi J., Chapman E.R., Link E., Binz T., Yamasaki S., De Camilli P.,
Suedhof T.C., Niemann H., Jahn R.;
"Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-
25.";
Nature 365:160-163(1993).
[9]
IDENTIFICATION OF SUBSTRATE (BOTULINUM NEUROTOXIN TYPE A AND BOTULINUM
NEUROTOXIN A LIGHT CHAIN), IDENTIFICATION OF SUBSTRATE, AND CATALYTIC
ACTIVITYSUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A LIGHT CHAIN).
STRAIN=Hall / Type A;
PubMed=8294407;
Binz T., Blasi J., Yamasaki S., Baumeister A., Link E., Suedhof T.C.,
Jahn R., Niemann H.;
"Proteolysis of SNAP-25 by types E and A botulinal neurotoxins.";
J. Biol. Chem. 269:1617-1620(1994).
[10]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND
GANGLIOSIDE-BINDING.
STRAIN=Hall / Type A;
PubMed=21849494; DOI=10.1074/jbc.M111.272054;
Benson M.A., Fu Z., Kim J.J., Baldwin M.R.;
"Unique ganglioside recognition strategies for clostridial
neurotoxins.";
J. Biol. Chem. 286:34015-34022(2011).
[11]
REVIEW.
PubMed=28356439; DOI=10.1124/pr.116.012658;
Pirazzini M., Rossetto O., Eleopra R., Montecucco C.;
"Botulinum neurotoxins: Biology, pharmacology, and toxicology.";
Pharmacol. Rev. 69:200-235(2017).
[12] {ECO:0000244|PDB:3BTA}
X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 2-1296, COFACTOR, SUBUNIT,
SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A LIGHT CHAIN AND BOTULINUM
NEUROTOXIN A HEAVY CHAIN), DOMAIN, AND DISULFIDE BOND.
STRAIN=Hall / Type A;
PubMed=9783750; DOI=10.1038/2338;
Lacy D.B., Tepp W., Cohen A.C., Dasgupta B.R., Stevens R.C.;
"Crystal structure of botulinum neurotoxin type A and implications for
toxicity.";
Nat. Struct. Biol. 5:898-902(1998).
[13] {ECO:0000244|PDB:2NYY, ECO:0000244|PDB:2NZ9}
X-RAY CRYSTALLOGRAPHY (2.61 ANGSTROMS) OF 2-1296 IN COMPLEX WITH ZINC
AND NEUTRALIZING ANTIBODY FRAGMENTS, COFACTOR, SUBUNIT, DOMAIN, AND
DISULFIDE BONDS.
STRAIN=Hall / Type A;
PubMed=17173035; DOI=10.1038/nbt1269;
Garcia-Rodriguez C., Levy R., Arndt J.W., Forsyth C.M., Razai A.,
Lou J., Geren I., Stevens R.C., Marks J.D.;
"Molecular evolution of antibody cross-reactivity for two subtypes of
type A botulinum neurotoxin.";
Nat. Biotechnol. 25:107-116(2007).
[14] {ECO:0000244|PDB:3FUO}
X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 871-1296, FUNCTION
(BOTULINUM NEUROTOXIN TYPE A), FUNCTION (BOTULINUM NEUROTOXIN A HEAVY
CHAIN), SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND
DOMAIN.
STRAIN=Hall / Type A;
PubMed=19476346; DOI=10.1021/bi9002138;
Fu Z., Chen C., Barbieri J.T., Kim J.J., Baldwin M.R.;
"Glycosylated SV2 and gangliosides as dual receptors for botulinum
neurotoxin serotype F.";
Biochemistry 48:5631-5641(2009).
[15] {ECO:0000244|PDB:3QIX, ECO:0000244|PDB:3QIY, ECO:0000244|PDB:3QIZ, ECO:0000244|PDB:3QJ0}
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 3-424 IN COMPLEX WITH ZINC
AND INHIBITORS, COFACTOR, AND ENZYME REGULATION.
STRAIN=Hall / ATCC 3502 / NCTC 13319 / Type A;
PubMed=21434688; DOI=10.1021/bi2001483;
Thompson A.A., Jiao G.S., Kim S., Thai A., Cregar-Hernandez L.,
Margosiak S.A., Johnson A.T., Han G.W., O'Malley S., Stevens R.C.;
"Structural characterization of three novel hydroxamate-based zinc
chelating inhibitors of the Clostridium botulinum serotype A
neurotoxin light chain metalloprotease reveals a compact binding site
resulting from 60/70 loop flexibility.";
Biochemistry 50:4019-4028(2011).
-!- 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: Limited hydrolysis of proteins of the
neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No
detected action on small molecule substrates.
{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};
-!- ENZYME 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}.
-!- WEB RESOURCE: Name=BOTOX product information Web site;
URL="http://www.botox.com/";
-!- WEB RESOURCE: Name=Protein Spotlight; Note=From sausages to
wrinkles - Issue 19 of February 2002;
URL="https://web.expasy.org/spotlight/back_issues/019";
-!- WEB RESOURCE: Name=BotDB - A Database Resource for Clostridial
Neurotoxins;
URL="https://botdb.abcc.ncifcrf.gov/";
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EMBL; AM412317; CAL82360.1; -; Genomic_DNA.
EMBL; CP000727; ABS38337.1; -; Genomic_DNA.
EMBL; M27892; AAA23269.1; -; Genomic_DNA.
PIR; A35294; BTCLAB.
PDB; 2NYY; X-ray; 2.61 A; A=2-1296.
PDB; 2NZ9; X-ray; 3.79 A; A/B=2-1296.
PDB; 3BTA; X-ray; 3.20 A; A=2-1296.
PDB; 3BWI; X-ray; 1.70 A; A=1-424.
PDB; 3C88; X-ray; 1.60 A; A=1-424.
PDB; 3C89; X-ray; 1.58 A; A=1-424.
PDB; 3C8A; X-ray; 1.52 A; A=1-424.
PDB; 3C8B; X-ray; 1.47 A; A=1-424.
PDB; 3DDA; X-ray; 1.50 A; A=1-424.
PDB; 3DDB; X-ray; 1.60 A; A=1-424.
PDB; 3DS9; X-ray; 1.76 A; A=1-417.
PDB; 3DSE; X-ray; 1.90 A; A=1-417.
PDB; 3FUO; X-ray; 1.80 A; A=871-1296.
PDB; 3K3Q; X-ray; 2.60 A; B=3-250, C=251-425.
PDB; 3QIX; X-ray; 2.41 A; A/B=3-424.
PDB; 3QIY; X-ray; 2.30 A; A=3-424.
PDB; 3QIZ; X-ray; 2.00 A; A=3-424.
PDB; 3QJ0; X-ray; 2.30 A; A=3-424.
PDB; 3QW5; X-ray; 1.60 A; A=1-424.
PDB; 3QW6; X-ray; 1.60 A; A=1-424.
PDB; 3QW7; X-ray; 1.50 A; A=1-424.
PDB; 3QW8; X-ray; 1.60 A; A=1-424.
PDB; 4EJ5; X-ray; 1.87 A; A=1-425.
PDB; 4EL4; X-ray; 1.20 A; A=1-425.
PDB; 4ELC; X-ray; 1.80 A; A=1-425.
PDB; 4KS6; X-ray; 1.93 A; A=1-425.
PDB; 4KTX; X-ray; 2.59 A; A=1-425.
PDB; 4KUF; X-ray; 1.70 A; A=1-425.
PDB; 4ZJX; X-ray; 1.94 A; A=1-424.
PDB; 5L21; X-ray; 1.68 A; A=872-1296.
PDBsum; 2NYY; -.
PDBsum; 2NZ9; -.
PDBsum; 3BTA; -.
PDBsum; 3BWI; -.
PDBsum; 3C88; -.
PDBsum; 3C89; -.
PDBsum; 3C8A; -.
PDBsum; 3C8B; -.
PDBsum; 3DDA; -.
PDBsum; 3DDB; -.
PDBsum; 3DS9; -.
PDBsum; 3DSE; -.
PDBsum; 3FUO; -.
PDBsum; 3K3Q; -.
PDBsum; 3QIX; -.
PDBsum; 3QIY; -.
PDBsum; 3QIZ; -.
PDBsum; 3QJ0; -.
PDBsum; 3QW5; -.
PDBsum; 3QW6; -.
PDBsum; 3QW7; -.
PDBsum; 3QW8; -.
PDBsum; 4EJ5; -.
PDBsum; 4EL4; -.
PDBsum; 4ELC; -.
PDBsum; 4KS6; -.
PDBsum; 4KTX; -.
PDBsum; 4KUF; -.
PDBsum; 4ZJX; -.
PDBsum; 5L21; -.
Proteomes; UP000001986; Chromosome.
PROSITE; PS00142; ZINC_PROTEASE; 1.
1: Evidence at protein level;
3D-structure; Complete proteome; Direct protein sequencing;
Disulfide bond; Host cell junction; Host cell membrane;
Host cytoplasm; Host cytoplasmic vesicle; Host membrane; Host synapse;
Hydrolase; Membrane; Metal-binding; Metalloprotease; Neurotoxin;
Pharmaceutical; Protease; Reference proteome; Secreted; Toxin;
Transmembrane; Transmembrane helix; Virulence; Zinc.
INIT_MET 1 1 Removed. {ECO:0000250|UniProtKB:P0DPI0}.
CHAIN 2 1296 Botulinum neurotoxin type A.
/FTId=PRO_0000444903.
CHAIN 2 448 Botulinum neurotoxin A light chain.
/FTId=PRO_0000308906.
CHAIN 449 1296 Botulinum neurotoxin A heavy chain.
/FTId=PRO_0000308907.
TRANSMEM 627 647 Helical. {ECO:0000255}.
TRANSMEM 656 676 Helical. {ECO:0000255}.
REGION 449 872 Translocation domain (TD).
{ECO:0000305|PubMed:17173035,
ECO:0000305|PubMed:9783750}.
REGION 492 545 Belt. {ECO:0000250|UniProtKB:P0DPI0}.
REGION 873 1092 N-terminus of receptor binding domain (N-
RBD). {ECO:0000305|PubMed:17173035,
ECO:0000305|PubMed:9783750}.
REGION 1093 1296 C-terminus of receptor binding domain (C-
RBD). {ECO:0000305|PubMed:17173035,
ECO:0000305|PubMed:9783750}.
MOTIF 1264 1267 Host ganglioside-binding motif.
{ECO:0000250|UniProtKB:P0DPI0}.
ACT_SITE 224 224 {ECO:0000255|PROSITE-ProRule:PRU10095}.
METAL 223 223 Zinc; via tele nitrogen; catalytic.
{ECO:0000244|PDB:2NYY,
ECO:0000244|PDB:2NZ9,
ECO:0000244|PDB:3BTA,
ECO:0000244|PDB:3QIX,
ECO:0000244|PDB:3QIY,
ECO:0000244|PDB:3QIZ,
ECO:0000244|PDB:3QJ0,
ECO:0000255|PROSITE-ProRule:PRU10095,
ECO:0000269|PubMed:17173035,
ECO:0000305|PubMed:9783750}.
METAL 227 227 Zinc; via tele nitrogen; catalytic.
{ECO:0000244|PDB:2NYY,
ECO:0000244|PDB:2NZ9,
ECO:0000244|PDB:3BTA,
ECO:0000244|PDB:3QIX,
ECO:0000244|PDB:3QIY,
ECO:0000244|PDB:3QIZ,
ECO:0000244|PDB:3QJ0,
ECO:0000255|PROSITE-ProRule:PRU10095,
ECO:0000269|PubMed:17173035,
ECO:0000305|PubMed:9783750}.
METAL 262 262 Zinc; catalytic. {ECO:0000244|PDB:2NYY,
ECO:0000244|PDB:2NZ9,
ECO:0000244|PDB:3BTA,
ECO:0000244|PDB:3QIX,
ECO:0000244|PDB:3QIY,
ECO:0000244|PDB:3QIZ,
ECO:0000244|PDB:3QJ0,
ECO:0000255|PROSITE-ProRule:PRU10095,
ECO:0000269|PubMed:17173035}.
DISULFID 430 454 Interchain (between light and heavy
chains). {ECO:0000244|PDB:2NYY,
ECO:0000244|PDB:2NZ9,
ECO:0000244|PDB:3BTA,
ECO:0000269|PubMed:17173035,
ECO:0000269|PubMed:9783750}.
DISULFID 1235 1280 {ECO:0000244|PDB:2NZ9,
ECO:0000244|PDB:3BTA,
ECO:0000269|PubMed:17173035,
ECO:0000269|PubMed:9783750}.
MUTAGEN 224 224 E->K,Q: Light chain no longer cleaves
SNAP25. {ECO:0000269|PubMed:8103915}.
CONFLICT 876 876 T -> L (in Ref. 4; AA sequence).
{ECO:0000305}.
CONFLICT 892 892 S -> K (in Ref. 4; AA sequence).
{ECO:0000305}.
CONFLICT 1218 1218 S -> Y (in Ref. 5; AA sequence).
{ECO:0000305}.
SEQUENCE 1296 AA; 149426 MW; DEA8CF2754AE43E6 CRC64;
MPFVNKQFNY KDPVNGVDIA YIKIPNAGQM QPVKAFKIHN KIWVIPERDT FTNPEEGDLN
PPPEAKQVPV SYYDSTYLST DNEKDNYLKG VTKLFERIYS TDLGRMLLTS IVRGIPFWGG
STIDTELKVI DTNCINVIQP DGSYRSEELN LVIIGPSADI IQFECKSFGH EVLNLTRNGY
GSTQYIRFSP DFTFGFEESL EVDTNPLLGA GKFATDPAVT LAHELIHAGH RLYGIAINPN
RVFKVNTNAY YEMSGLEVSF EELRTFGGHD AKFIDSLQEN EFRLYYYNKF KDIASTLNKA
KSIVGTTASL QYMKNVFKEK YLLSEDTSGK FSVDKLKFDK LYKMLTEIYT EDNFVKFFKV
LNRKTYLNFD KAVFKINIVP KVNYTIYDGF NLRNTNLAAN FNGQNTEINN MNFTKLKNFT
GLFEFYKLLC VRGIITSKTK SLDKGYNKAL NDLCIKVNNW DLFFSPSEDN FTNDLNKGEE
ITSDTNIEAA EENISLDLIQ QYYLTFNFDN EPENISIENL SSDIIGQLEL MPNIERFPNG
KKYELDKYTM FHYLRAQEFE HGKSRIALTN SVNEALLNPS RVYTFFSSDY VKKVNKATEA
AMFLGWVEQL VYDFTDETSE VSTTDKIADI TIIIPYIGPA LNIGNMLYKD DFVGALIFSG
AVILLEFIPE IAIPVLGTFA LVSYIANKVL TVQTIDNALS KRNEKWDEVY KYIVTNWLAK
VNTQIDLIRK KMKEALENQA EATKAIINYQ YNQYTEEEKN NINFNIDDLS SKLNESINKA
MININKFLNQ CSVSYLMNSM IPYGVKRLED FDASLKDALL KYIYDNRGTL IGQVDRLKDK
VNNTLSTDIP FQLSKYVDNQ RLLSTFTEYI KNIINTSILN LRYESNHLID LSRYASKINI
GSKVNFDPID KNQIQLFNLE SSKIEVILKN AIVYNSMYEN FSTSFWIRIP KYFNSISLNN
EYTIINCMEN NSGWKVSLNY GEIIWTLQDT QEIKQRVVFK YSQMINISDY INRWIFVTIT
NNRLNNSKIY INGRLIDQKP ISNLGNIHAS NNIMFKLDGC RDTHRYIWIK YFNLFDKELN
EKEIKDLYDN QSNSGILKDF WGDYLQYDKP YYMLNLYDPN KYVDVNNVGI RGYMYLKGPR
GSVMTTNIYL NSSLYRGTKF IIKKYASGNK DNIVRNNDRV YINVVVKNKE YRLATNASQA
GVEKILSALE IPDVGNLSQV VVMKSKNDQG ITNKCKMNLQ DNNGNDIGFI GFHQFNNIAK
LVASNWYNRQ IERSSRTLGC SWEFIPVDDG WGERPL

BXA1_CLOBO Reviewed; 1296 AA.
P0DPI0; A5HZZ9; A7G1U9; P01561; P10845; P18639;
18-JUL-2018, integrated into UniProtKB/Swiss-Prot.
18-JUL-2018, sequence version 1.
18-JUL-2018, entry version 1.
RecName: Full=Botulinum neurotoxin type A;
Short=BoNT/A;
AltName: Full=Bontoxilysin-A;
Short=BOTOX;
Contains:
RecName: Full=Botulinum neurotoxin A light chain;
Short=LC;
EC=3.4.24.69 {ECO:0000269|PubMed:8243676};
Contains:
RecName: Full=Botulinum neurotoxin A heavy chain;
Short=HC;
Flags: Precursor;
Name=botA {ECO:0000303|PubMed:2185020};
Synonyms=atx {ECO:0000303|PubMed:8521962},
bonT {ECO:0000303|PubMed:8863443};
Clostridium botulinum.
Bacteria; Firmicutes; Clostridia; Clostridiales; Clostridiaceae;
Clostridium.
NCBI_TaxID=1491;
[1]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
STRAIN=NCTC 2916 / Type A;
PubMed=2185020; DOI=10.1111/j.1432-1033.1990.tb15461.x;
Thompson D.E., Brehm J.K., Oultram J.D., Swinfield T.-J., Shone C.C.,
Atkinson T., Melling J., Minton N.P.;
"The complete amino acid sequence of the Clostridium botulinum type A
neurotoxin, deduced by nucleotide sequence analysis of the encoding
gene.";
Eur. J. Biochem. 189:73-81(1990).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC DNA].
STRAIN=62A / Type A;
PubMed=2160960;
Binz T., Kurazono H., Wille M., Frevert J., Wernars K., Niemann H.;
"The complete sequence of botulinum neurotoxin type A and comparison
with other clostridial neurotoxins.";
J. Biol. Chem. 265:9153-9158(1990).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-66.
STRAIN=62A / Type A;
PubMed=8863443; DOI=10.1099/00207713-46-4-1105;
East A.K., Bhandari M., Stacey J.M., Campbell K.D., Collins M.D.;
"Organization and phylogenetic interrelationships of genes encoding
components of the botulinum toxin complex in proteolytic Clostridium
botulinum types A, B, and F: evidence of chimeric sequences in the
gene encoding the nontoxic nonhemagglutinin component.";
Int. J. Syst. Bacteriol. 46:1105-1112(1996).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-19.
STRAIN=NIH / Type A;
PubMed=8521962; DOI=10.1016/0014-5793(95)01241-5;
Fujita R., Fujinaga Y., Inoue K., Nakajima H., Kumon H., Oguma K.;
"Molecular characterization of two forms of nontoxic-nonhemagglutinin
components of Clostridium botulinum type A progenitor toxins.";
FEBS Lett. 376:41-44(1995).
[5]
PROTEIN SEQUENCE OF 2-18 AND 449-458, AND SUBCELLULAR LOCATION
(BOTULINUM NEUROTOXIN A LIGHT CHAIN AND BOTULINUM NEUROTOXIN A HEAVY
CHAIN).
STRAIN=Type A;
PubMed=6370252; DOI=10.1016/0006-291X(84)90858-1;
Schmidt J.J., Sartymoorthy V., Dasgupta B.R.;
"Partial amino acid sequence of the heavy and light chains of
botulinum neurotoxin type A.";
Biochem. Biophys. Res. Commun. 119:900-904(1984).
[6]
PROTEIN SEQUENCE OF 2-47.
Dasgupta B.R., Foley J., Niece R.;
"Partial sequence of the light chain of botulinum neurotoxin type A.";
Biochemistry 26:4162-4162(1987).
[7]
PROTEIN SEQUENCE OF 2-6 AND 445-457.
STRAIN=Type A;
PubMed=2126206; DOI=10.1016/0300-9084(90)90048-L;
Dasgupta B.R., Dekleva M.L.;
"Botulinum neurotoxin type A: sequence of amino acids at the N-
terminus and around the nicking site.";
Biochimie 72:661-664(1990).
[8]
PROTEIN SEQUENCE OF 251-257; 267-273 AND 420-448, COFACTOR, AND
PROTEOLYTIC CLEAVAGE.
PubMed=11565902;
Ahmed S.A., Byrne M.P., Jensen M., Hines H.B., Brueggemann E.,
Smith L.A.;
"Enzymatic autocatalysis of botulinum A neurotoxin light chain.";
J. Protein Chem. 20:221-231(2001).
[9]
PROTEIN SEQUENCE OF 449-483.
STRAIN=NCTC 2916 / Type A;
PubMed=3896784; DOI=10.1111/j.1432-1033.1985.tb09070.x;
Shone C.C., Hambleton P., Melling J.;
"Inactivation of Clostridium botulinum type A neurotoxin by trypsin
and purification of two tryptic fragments. Proteolytic action near the
COOH-terminus of the heavy subunit destroys toxin-binding activity.";
Eur. J. Biochem. 151:75-82(1985).
[10]
FUNCTION (BOTULINUM NEUROTOXIN TYPE A).
STRAIN=4587 / Type A;
PubMed=15394302; DOI=10.1113/jphysiol.1949.sp004364;
Burgen A.S., Dickens F., Zatman L.J.;
"The action of botulinum toxin on the neuro-muscular junction.";
J. Physiol. (Lond.) 109:10-24(1949).
[11]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), SUBCELLULAR LOCATION
(BOTULINUM NEUROTOXIN TYPE A AND BOTULINUM NEUROTOXIN A HEAVY CHAIN),
AND ENZYME REGULATION.
STRAIN=Type A;
PubMed=6694738;
Dolly J.O., Black J., Williams R.S., Melling J.;
"Acceptors for botulinum neurotoxin reside on motor nerve terminals
and mediate its internalization.";
Nature 307:457-460(1984).
[12]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND DOMAIN.
STRAIN=Type A;
PubMed=2446925;
Blaustein R.O., Germann W.J., Finkelstein A., DasGupta B.R.;
"The N-terminal half of the heavy chain of botulinum type A neurotoxin
forms channels in planar phospholipid bilayers.";
FEBS Lett. 226:115-120(1987).
[13]
IDENTIFICATION AS A ZINC-BINDING PROTEIN, AND COFACTOR.
STRAIN=Type A;
PubMed=1429690;
Schiavo G., Rossetto O., Santucci A., Dasgupta B.R., Montecucco C.;
"Botulinum neurotoxins are zinc proteins.";
J. Biol. Chem. 267:23479-23483(1992).
[14]
HOST RANGE, AND EPIDEMIOLOGY.
PubMed=1431246;
Woodruff B.A., Griffin P.M., McCroskey L.M., Smart J.F.,
Wainwright R.B., Bryant R.G., Hutwagner L.C., Hatheway C.L.;
"Clinical and laboratory comparison of botulism from toxin types A, B,
and E in the United States, 1975-1988.";
J. Infect. Dis. 166:1281-1286(1992).
[15]
FUNCTION (BOTULINUM NEUROTOXIN A LIGHT CHAIN), IDENTIFICATION OF
SUBSTRATE, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION (BOTULINUM
NEUROTOXIN A LIGHT CHAIN).
STRAIN=Type A;
PubMed=8243676; DOI=10.1016/0014-5793(93)80448-4;
Schiavo G., Santtuci A., Dasgupta B.R., Mehta P.P., Jontes J.,
Benfenati F., Wilson M.C., Montecucco C.;
"Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct
COOH-terminal peptide bonds.";
FEBS Lett. 335:99-103(1993).
[16]
FUNCTION (BOTULINUM NEUROTOXIN TYPE A AND BOTULINUM NEUROTOXIN A LIGHT
CHAIN), CATALYTIC ACTIVITY, COFACTOR, SUBUNIT, SUBCELLULAR LOCATION
(BOTULINUM NEUROTOXIN A LIGHT CHAIN), DOMAIN, AND MUTAGENESIS OF
HIS-227.
STRAIN=63A / Type A;
PubMed=7578132; DOI=10.1021/bi00046a025;
Zhou L., de Paiva A., Liu D., Aoki R., Dolly J.O.;
"Expression and purification of the light chain of botulinum
neurotoxin A: a single mutation abolishes its cleavage of SNAP-25 and
neurotoxicity after reconstitution with the heavy chain.";
Biochemistry 34:15175-15181(1995).
[17]
SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN TYPE A), AND INDUCTION.
STRAIN=62A / Type A;
PubMed=7592120;
Call J.E., Cooke P.H., Miller A.J.;
"In situ characterization of Clostridium botulinum neurotoxin
synthesis and export.";
J. Appl. Bacteriol. 79:257-263(1995).
[18]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND SUBCELLULAR
LOCATION (BOTULINUM NEUROTOXIN A HEAVY CHAIN).
STRAIN=62A / P64 / Type A;
PubMed=10413679;
Lalli G., Herreros J., Osborne S.L., Montecucco C., Rossetto O.,
Schiavo G.;
"Functional characterisation of tetanus and botulinum neurotoxins
binding domains.";
J. Cell Sci. 112:2715-2724(1999).
[19]
FUNCTION (BOTULINUM NEUROTOXIN A LIGHT CHAIN), SUBSTRATE SPECIFICITY,
CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A
LIGHT CHAIN).
STRAIN=62A / P64 / Type A;
PubMed=9886085;
Vaidyanathan V.V., Yoshino K., Jahnz M., Doerries C., Bade S.,
Nauenburg S., Niemann H., Binz T.;
"Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C,
and E: domains and amino acid residues controlling the formation of
enzyme-substrate complexes and cleavage.";
J. Neurochem. 72:327-337(1999).
[20]
FUNCTION (BOTULINUM NEUROTOXIN A LIGHT CHAIN), ACTIVE SITE, CATALYTIC
ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF GLU-224.
STRAIN=Type A;
PubMed=10694409; DOI=10.1021/bi992321x;
Li L., Binz T., Niemann H., Singh B.R.;
"Probing the mechanistic role of glutamate residue in the zinc-binding
motif of type A botulinum neurotoxin light chain.";
Biochemistry 39:2399-2405(2000).
[21]
BIOTECHNOLOGY.
STRAIN=NCTC 2916 / Type A;
PubMed=10768948;
Chaddock J.A., Purkiss J.R., Friis L.M., Broadbridge J.D.,
Duggan M.J., Fooks S.J., Shone C.C., Quinn C.P., Foster K.A.;
"Inhibition of vesicular secretion in both neuronal and nonneuronal
cells by a retargeted endopeptidase derivative of Clostridium
botulinum neurotoxin type A.";
Infect. Immun. 68:2587-2593(2000).
[22]
FUNCTION (BOTULINUM NEUROTOXIN A LIGHT CHAIN), COFACTOR, AND
MUTAGENESIS OF GLU-262; PHE-266 AND TYR-366.
STRAIN=P64 / Type A;
PubMed=11700044; DOI=10.1006/bbrc.2001.5911;
Rigoni M., Caccin P., Johnson E.A., Montecucco C., Rossetto O.;
"Site-directed mutagenesis identifies active-site residues of the
light chain of botulinum neurotoxin type A.";
Biochem. Biophys. Res. Commun. 288:1231-1237(2001).
[23]
FUNCTION (BOTULINUM NEUROTOXIN A LIGHT CHAIN), BIOPHYSICOCHEMICAL
PROPERTIES, AND MUTAGENESIS OF GLU-351; ARG-363 AND TYR-366.
STRAIN=62A / P64 / Type A;
PubMed=11827515;
Binz T., Bade S., Rummel A., Kollewe A., Alves J.;
"Arg(362) and Tyr(365) of the botulinum neurotoxin type a light chain
are involved in transition state stabilization.";
Biochemistry 41:1717-1723(2002).
[24]
REQUIREMENT FOR GANGLIOSIDES FOR ACTIVITY (BOTULINUM NEUROTOXIN TYPE
A).
STRAIN=Type A;
PubMed=12089155; DOI=10.1074/jbc.M205258200;
Yowler B.C., Kensinger R.D., Schengrund C.L.;
"Botulinum neurotoxin A activity is dependent upon the presence of
specific gangliosides in neuroblastoma cells expressing synaptotagmin
I.";
J. Biol. Chem. 277:32815-32819(2002).
[25]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), GANGLIOSIDE-BINDING
(BOTULINUM NEUROTOXIN A HEAVY CHAIN), MUTAGENESIS OF GLU-1203;
HIS-1253; SER-1264; TRP-1266 AND TYR-1267, AND LIPID-BINDING.
STRAIN=62A / Type A;
PubMed=14731268; DOI=10.1046/j.1365-2958.2003.03872.x;
Rummel A., Mahrhold S., Bigalke H., Binz T.;
"The HCC-domain of botulinum neurotoxins A and B exhibits a singular
ganglioside binding site displaying serotype specific carbohydrate
interaction.";
Mol. Microbiol. 51:631-643(2004).
[26]
IDENTIFICATION OF HOST RECEPTOR (BOTULINUM NEUROTOXIN TYPE A AND
BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND INTERACTION WITH HOST SV2C.
STRAIN=Type A;
PubMed=16545378; DOI=10.1016/j.febslet.2006.02.074;
Mahrhold S., Rummel A., Bigalke H., Davletov B., Binz T.;
"The synaptic vesicle protein 2C mediates the uptake of botulinum
neurotoxin A into phrenic nerves.";
FEBS Lett. 580:2011-2014(2006).
[27]
IDENTIFICATION OF HOST RECEPTOR (BOTULINUM NEUROTOXIN TYPE A), AND
INTERACTION WITH HOST SV2 PROTEINS.
STRAIN=Type A;
PubMed=16543415; DOI=10.1126/science.1123654;
Dong M., Yeh F., Tepp W.H., Dean C., Johnson E.A., Janz R.,
Chapman E.R.;
"SV2 is the protein receptor for botulinum neurotoxin A.";
Science 312:592-596(2006).
[28]
FUNCTION (BOTULINUM NEUROTOXIN A LIGHT AND HEAVY CHAIN), DOMAIN, AND
DISULFIDE BOND.
PubMed=17666397; DOI=10.1074/jbc.M703619200;
Fischer A., Montal M.;
"Crucial role of the disulfide bridge between botulinum neurotoxin
light and heavy chains in protease translocation across membranes.";
J. Biol. Chem. 282:29604-29611(2007).
[29]
DISCUSSION OF BELT FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND
DOMAIN.
PubMed=17907800; DOI=10.1371/journal.ppat.0030113;
Brunger A.T., Breidenbach M.A., Jin R., Fischer A., Santos J.S.,
Montal M.;
"Botulinum neurotoxin heavy chain belt as an intramolecular chaperone
for the light chain.";
PLoS Pathog. 3:1191-1194(2007).
[30]
IDENTIFICATION OF HOST RECEPTOR (BOTULINUM NEUROTOXIN TYPE A), AND
INTERACTION WITH HOST SV2 PROTEINS.
STRAIN=Type A;
PubMed=18815274; DOI=10.1091/mbc.E08-07-0765;
Dong M., Liu H., Tepp W.H., Johnson E.A., Janz R., Chapman E.R.;
"Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin
E into neurons.";
Mol. Biol. Cell 19:5226-5237(2008).
[31]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND DOMAIN.
STRAIN=Type A;
PubMed=19096517; DOI=10.1371/journal.ppat.1000245;
Fischer A., Mushrush D.J., Lacy D.B., Montal M.;
"Botulinum neurotoxin devoid of receptor binding domain translocates
active protease.";
PLoS Pathog. 4:E1000245-E1000245(2008).
[32]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), DOMAIN, AND
PHOSPHATIDYLINOSITOL-BINDING.
STRAIN=Type A;
PubMed=19161982; DOI=10.1016/j.bbrc.2009.01.037;
Muraro L., Tosatto S., Motterlini L., Rossetto O., Montecucco C.;
"The N-terminal half of the receptor domain of botulinum neurotoxin A
binds to microdomains of the plasma membrane.";
Biochem. Biophys. Res. Commun. 380:76-80(2009).
[33]
FUNCTION (BOTULINUM NEUROTOXIN TYPE A), FUNCTION (BOTULINUM NEUROTOXIN
A HEAVY CHAIN), INTERACTION WITH HOST SV2 PROTEINS, AND MUTAGENESIS OF
TRP-1266.
PubMed=19650874; DOI=10.1111/j.1471-4159.2009.06298.x;
Rummel A., Haefner K., Mahrhold S., Darashchonak N., Holt M., Jahn R.,
Beermann S., Karnath T., Bigalke H., Binz T.;
"Botulinum neurotoxins C, E and F bind gangliosides via a conserved
binding site prior to stimulation-dependent uptake with botulinum
neurotoxin F utilising the three isoforms of SV2 as second receptor.";
J. Neurochem. 110:1942-1954(2009).
[34]
FUNCTION (BOTULINUM NEUROTOXIN TYPE A), AND SUBCELLULAR LOCATION
(BOTULINUM NEUROTOXIN A HEAVY CHAIN).
STRAIN=Type A;
PubMed=21632541; DOI=10.1074/jbc.M111.254086;
Kroken A.R., Karalewitz A.P., Fu Z., Kim J.J., Barbieri J.T.;
"Novel ganglioside-mediated entry of botulinum neurotoxin serotype D
into neurons.";
J. Biol. Chem. 286:26828-26837(2011).
[35]
FUNCTION (BOTULINUM NEUROTOXIN TYPE A), SUBCELLULAR LOCATION
(BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND ENZYME REGULATION.
PubMed=21832053; DOI=10.1074/jbc.M111.283879;
Harper C.B., Martin S., Nguyen T.H., Daniels S.J., Lavidis N.A.,
Popoff M.R., Hadzic G., Mariana A., Chau N., McCluskey A.,
Robinson P.J., Meunier F.A.;
"Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in
neurons and delays botulism.";
J. Biol. Chem. 286:35966-35976(2011).
[36]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), TRANSCYTOSIS ACROSS
HOST CELLS, BIOTECHNOLOGY, AND MUTAGENESIS OF HIS-1253;
1266-TRP-TYR-1267; TRP-1266 AND TYR-1267.
STRAIN=62A / Type A;
PubMed=21106906; DOI=10.1124/jpet.110.175018;
Elias M., Al-Saleem F., Ancharski D.M., Singh A., Nasser Z.,
Olson R.M., Simpson L.L.;
"Evidence that botulinum toxin receptors on epithelial cells and
neuronal cells are not identical: implications for development of a
non-neurotropic vaccine.";
J. Pharmacol. Exp. Ther. 336:605-612(2011).
[37]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND DOMAIN.
STRAIN=Type A;
PubMed=22158863; DOI=10.1074/jbc.C111.319400;
Fischer A., Sambashivan S., Brunger A.T., Montal M.;
"Beltless translocation domain of botulinum neurotoxin A embodies a
minimum ion-conductive channel.";
J. Biol. Chem. 287:1657-1661(2012).
[38]
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND SUBCELLULAR
LOCATION (BOTULINUM NEUROTOXIN A HEAVY CHAIN).
PubMed=23471747; DOI=10.1007/s12035-013-8423-9;
Colasante C., Rossetto O., Morbiato L., Pirazzini M., Molgo J.,
Montecucco C.;
"Botulinum neurotoxin type A is internalized and translocated from
small synaptic vesicles at the neuromuscular junction.";
Mol. Neurobiol. 48:120-127(2013).
[39]
POSSIBLE IDENTIFICATION OF HOST RECEPTOR (BOTULINUM NEUROTOXIN TYPE
A).
STRAIN=Type A;
PubMed=23696738; DOI=10.1371/journal.ppat.1003369;
Jacky B.P., Garay P.E., Dupuy J., Nelson J.B., Cai B., Molina Y.,
Wang J., Steward L.E., Broide R.S., Francis J., Aoki K.R.,
Stevens R.C., Fernandez-Salas E.;
"Identification of fibroblast growth factor receptor 3 (FGFR3) as a
protein receptor for botulinum neurotoxin serotype A (BoNT/A).";
PLoS Pathog. 9:E1003369-E1003369(2013).
[40]
RECOGNITION OF RECEPTOR (BOTULINUM NEUROTOXIN A HEAVY CHAIN), AND
SUBUNIT.
STRAIN=62A / Type A;
PubMed=27313224; DOI=10.1042/BCJ20160439;
Mahrhold S., Bergstroem T., Stern D., Dorner B.G., Aastot C.,
Rummel A.;
"Only the complex N559-glycan in the synaptic vesicle glycoprotein 2C
mediates high affinity binding to botulinum neurotoxin serotype A1.";
Biochem. J. 473:2645-2654(2016).
[41]
REVIEW.
PubMed=23518040; DOI=10.1016/j.toxicon.2013.02.014;
Simpson L.;
"The life history of a botulinum toxin molecule.";
Toxicon 68:40-59(2013).
[42]
REVIEW.
PubMed=28356439; DOI=10.1124/pr.116.012658;
Pirazzini M., Rossetto O., Eleopra R., Montecucco C.;
"Botulinum neurotoxins: Biology, pharmacology, and toxicology.";
Pharmacol. Rev. 69:200-235(2017).
[43] {ECO:0000244|PDB:1XTF, ECO:0000244|PDB:1XTG}
X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 2-420 IN COMPLEX WITH ZINC
WITH AND WITHOUT SUBSTRATE, FUNCTION (BOTULINUM NEUROTOXIN A LIGHT
CHAIN), SUBSTRATE SPECIFICITY, AND COFACTOR.
STRAIN=Type A;
PubMed=15592454; DOI=10.1038/nature03123;
Breidenbach M.A., Brunger A.T.;
"Substrate recognition strategy for botulinum neurotoxin serotype A.";
Nature 432:925-929(2004).
[44]
STRUCTURE BY ELECTRON MICROSCOPY (24.0 ANGSTROMS), AND DOMAIN.
STRAIN=Type A;
PubMed=18032388; DOI=10.1074/jbc.M707917200;
Fischer A., Garcia-Rodriguez C., Geren I., Lou J., Marks J.D.,
Nakagawa T., Montal M.;
"Molecular architecture of botulinum neurotoxin E revealed by single
particle electron microscopy.";
J. Biol. Chem. 283:3997-4003(2008).
[45] {ECO:0000244|PDB:2VU9, ECO:0000244|PDB:2VUA}
X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 874-1296 IN COMPLEX WITH
GANGLIOSIDE GT1B ANALOG, FUNCTION (BOTULINUM NEUROTOXIN A HEAVY
CHAIN), AND GANGLIOSIDE-BINDING.
STRAIN=Type A;
PubMed=18704164; DOI=10.1371/JOURNAL.PPAT.1000129;
Stenmark P., Dupuy J., Imamura A., Kiso M., Stevens R.C.;
"Crystal structure of botulinum neurotoxin type A in complex with the
cell surface co-receptor GT1b-insight into the toxin-neuron
interaction.";
PLoS Pathog. 4:e1000129-e1000129(2008).
[46] {ECO:0000244|PDB:2W2D}
X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 1-445 AND 447-877 IN COMPLEX
WITH ZINC, FUNCTION (BOTULINUM NEUROTOXIN A LIGHT AND HEAVY CHAIN),
COFACTOR, DOMAIN, AND DISULFIDE BONDS.
STRAIN=NCTC 2916 / Type A;
PubMed=19351593; DOI=10.1016/J.BBRC.2009.02.003;
Masuyer G., Thiyagarajan N., James P.L., Marks P.M., Chaddock J.A.,
Acharya K.R.;
"Crystal structure of a catalytically active, non-toxic endopeptidase
derivative of Clostridium botulinum toxin A.";
Biochem. Biophys. Res. Commun. 381:50-53(2009).
[47] {ECO:0000244|PDB:3V0A, ECO:0000244|PDB:3V0B, ECO:0000244|PDB:3V0C}
X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) IN COMPLEX WITH ZINC AND NTNHA,
FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN), COFACTOR, SUBUNIT,
DOMAIN, DISULFIDE BONDS, AND MUTAGENESIS OF 861-ARG--LYS-871;
862-LEU--THR-867; GLU-982; LYS-1000; ASP-1037; ASP-1118 AND ASP-1171.
STRAIN=Type A;
PubMed=22363010; DOI=10.1126/science.1214270;
Gu S., Rumpel S., Zhou J., Strotmeier J., Bigalke H., Perry K.,
Shoemaker C.B., Rummel A., Jin R.;
"Botulinum neurotoxin is shielded by NTNHA in an interlocked
complex.";
Science 335:977-981(2012).
[48] {ECO:0000244|PDB:4JRA}
X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 871-1296 IN COMPLEX WITH
SV2C RECEPTOR FRAGMENT, FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN),
SUBUNIT, SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN A HEAVY CHAIN),
AND MUTAGENESIS OF 1145-THR-THR-1146; ARG-1156 AND ARG-1294.
STRAIN=Type A;
PubMed=24240280; DOI=10.1038/nature12732;
Benoit R.M., Frey D., Hilbert M., Kevenaar J.T., Wieser M.M.,
Stirnimann C.U., McMillan D., Ceska T., Lebon F., Jaussi R.,
Steinmetz M.O., Schertler G.F., Hoogenraad C.C., Capitani G.,
Kammerer R.A.;
"Structural basis for recognition of synaptic vesicle protein 2C by
botulinum neurotoxin A.";
Nature 505:108-111(2014).
[49] {ECO:0000244|PDB:5JLV, ECO:0000244|PDB:5JMC}
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 872-1296 IN COMPLEX WITH
HUMAN AND SV2C RECEPTOR, FUNCTION (BOTULINUM NEUROTOXIN TYPE A AND
BOTULINUM NEUROTOXIN A HEAVY CHAIN), SV2 GLYCAN-BINDING, AND
MUTAGENESIS OF PHE-953; HIS-1064; 1145-THR-THR-1146; ARG-1156;
GLY-1292 AND ARG-1294.
STRAIN=Type A;
PubMed=27294781; DOI=10.1038/nsmb.3245;
Yao G., Zhang S., Mahrhold S., Lam K.H., Stern D., Bagramyan K.,
Perry K., Kalkum M., Rummel A., Dong M., Jin R.;
"N-linked glycosylation of SV2 is required for binding and uptake of
botulinum neurotoxin A.";
Nat. Struct. Mol. Biol. 23:656-662(2016).
[50] {ECO:0000244|PDB:5TPB, ECO:0000244|PDB:5TPC}
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 876-1296 IN COMPLEX WITH
GANGLIOSIDE ANALOG, AND FUNCTION (BOTULINUM NEUROTOXIN A HEAVY CHAIN).
STRAIN=Type A;
PubMed=27958736; DOI=10.1021/jacs.6b09534;
Hamark C., Berntsson R.P., Masuyer G., Henriksson L.M., Gustafsson R.,
Stenmark P., Widmalm G.;
"Glycans confer specificity to the recognition of ganglioside
receptors by botulinum neurotoxin A.";
J. Am. Chem. Soc. 139:218-230(2017).
[51] {ECO:0000244|PDB:5MK6, ECO:0000244|PDB:5MK7}
X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 871-1296, AND DISULFIDE
BOND.
PubMed=29576992; DOI=10.7717/peerj.4552;
Davies J.R., Hackett G.S., Liu S.M., Acharya K.R.;
"High resolution crystal structures of the receptor-binding domain of
Clostridium botulinum neurotoxin serotypes A and FA.";
PeerJ 6:E4552-E4552(2018).
-!- 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: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). {ECO:0000269|PubMed:12089155,
ECO:0000269|PubMed:15394302, ECO:0000269|PubMed:16543415,
ECO:0000269|PubMed:16545378, ECO:0000269|PubMed:17666397,
ECO:0000269|PubMed:18815274, ECO:0000269|PubMed:19096517,
ECO:0000269|PubMed:19650874, ECO:0000269|PubMed:21632541,
ECO:0000269|PubMed:21832053, ECO:0000269|PubMed:23696738,
ECO:0000269|PubMed:27294781, ECO:0000269|PubMed:7578132}.
-!- FUNCTION: Botulinum neurotoxin A light chain: Has proteolytic
activity (PubMed:7578132). After translocation into the eukaryotic
host cytosol LC hydrolyzes the '197-Gln-|-Arg-198' bond in SNAP25,
blocking neurotransmitter release (PubMed:8243676, PubMed:7578132,
PubMed:9886085, PubMed:10694409, PubMed:11700044, PubMed:11827515,
PubMed:19351593). Recognizes the '146-Met--Gly-155' region of
SNAP25, which confers substrate specificity (PubMed:9886085,
PubMed:15592454). Hydrolyzes the '202-Thr-|-Arg-203' bond of mouse
SNAP23, but not in human which has a different sequence
(PubMed:9886085). Reduction of the interchain disulfide bond
occurs in the host cytosol and probably prevents
retrotranslocation into the synaptic vesicle (PubMed:17666397).
Has slow (occurs over 4 weeks) autocatalytic cleavage, however it
is not clear if this is physiologically relevant
(PubMed:11565902). {ECO:0000269|PubMed:10694409,
ECO:0000269|PubMed:11565902, ECO:0000269|PubMed:11700044,
ECO:0000269|PubMed:11827515, ECO:0000269|PubMed:15592454,
ECO:0000269|PubMed:17666397, ECO:0000269|PubMed:7578132,
ECO:0000269|PubMed:8243676, ECO:0000269|PubMed:9886085,
ECO:0000305|PubMed:19351593}.
-!- 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).
{ECO:0000269|PubMed:10413679, ECO:0000269|PubMed:14731268,
ECO:0000269|PubMed:16545378, ECO:0000269|PubMed:17666397,
ECO:0000269|PubMed:18704164, ECO:0000269|PubMed:19096517,
ECO:0000269|PubMed:19161982, ECO:0000269|PubMed:19351593,
ECO:0000269|PubMed:19650874, ECO:0000269|PubMed:21106906,
ECO:0000269|PubMed:22158863, ECO:0000269|PubMed:22363010,
ECO:0000269|PubMed:23471747, ECO:0000269|PubMed:24240280,
ECO:0000269|PubMed:27294781, ECO:0000269|PubMed:27313224,
ECO:0000269|PubMed:27958736, ECO:0000269|PubMed:6694738,
ECO:0000305|PubMed:17907800, ECO:0000305|PubMed:2446925}.
-!- CATALYTIC ACTIVITY: Limited hydrolysis of proteins of the
neuroexocytosis apparatus, synaptobrevins, SNAP25 or syntaxin. No
detected action on small molecule substrates.
{ECO:0000269|PubMed:10694409, ECO:0000269|PubMed:7578132,
ECO:0000269|PubMed:8243676, ECO:0000269|PubMed:9886085}.
-!- COFACTOR:
Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
Evidence={ECO:0000269|PubMed:11565902,
ECO:0000269|PubMed:11700044, ECO:0000269|PubMed:1429690,
ECO:0000269|PubMed:15592454, ECO:0000269|PubMed:19351593,
ECO:0000269|PubMed:22363010, ECO:0000269|PubMed:7578132};
Note=Binds 1 zinc ion per subunit (PubMed:1429690,
PubMed:11700044, PubMed:15592454, PubMed:19351593,
PubMed:22363010). {ECO:0000269|PubMed:11700044,
ECO:0000269|PubMed:1429690, ECO:0000269|PubMed:15592454,
ECO:0000269|PubMed:19351593, ECO:0000269|PubMed:22363010};
-!- ENZYME REGULATION: Toxin internalization is inhibited by azide or
dinitrophenol or at 4 degrees Celsius (PubMed:6694738). Dynamin
(DNM) inhibitors abolish toxin uptake (PubMed:21832053).
{ECO:0000269|PubMed:21832053, ECO:0000269|PubMed:6694738}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=41 uM for purified SNAP25 with isolated botulinum neurotoxin
A light chain {ECO:0000269|PubMed:10694409};
KM=9.8 uM for purified SNAP25 with isolated botulinum neurotoxin
A light chain {ECO:0000269|PubMed:11827515};
Note=kcat is 140 min(-1) (PubMed:10694409). kcat is 1026 (-1)
(PubMed:11827515). {ECO:0000269|PubMed:10694409,
ECO:0000269|PubMed:11827515};
-!- SUBUNIT: Heterodimer; disulfide-linked heterodimer of a light
chain (LC) and heavy chain (HC) (PubMed:7578132). Interacts with
glycosylated host synaptic vesicle glycoproteins SV2A, SV2B and
SV2C which serve as coreceptors (PubMed:16543415, PubMed:18815274,
PubMed:19650874, PubMed:24240280, PubMed:27313224). Glycosylation
of 'Asn-559' in SV2C contributes a 12-fold increase in affinity to
this interaction (PubMed:27313224). Depolarization of target
tissue with high levels of K(+) leads to greater levels of
receptor exposure (PubMed:16543415). In vitro addition of
gangliosides increases SV2-toxin interaction (PubMed:16543415).
Forms a highly interlocked heterodimer with NTNHA at pH 6.0 but
not at pH 7.5 called the minimally functional progenitor toxin
complex (M-PTC) (PubMed:22363010). The PTC is thought to protect
toxin in the host acidic gastrointestinal tract, facilitate
transcytosis across the intestinal barrier and release at neutral
pH as is found in the bloodstream (PubMed:22363010).
{ECO:0000269|PubMed:16543415, ECO:0000269|PubMed:16545378,
ECO:0000269|PubMed:18815274, ECO:0000269|PubMed:19650874,
ECO:0000269|PubMed:22363010, ECO:0000269|PubMed:24240280,
ECO:0000269|PubMed:27313224, ECO:0000269|PubMed:7578132,
ECO:0000305|PubMed:22363010}.
-!- SUBCELLULAR LOCATION: Botulinum neurotoxin type A: Secreted
{ECO:0000269|PubMed:7592120}. Secreted, cell wall
{ECO:0000269|PubMed:7592120}. Host cell junction, host synapse,
host presynaptic cell membrane {ECO:0000269|PubMed:6694738}.
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).
{ECO:0000269|PubMed:6694738, ECO:0000269|PubMed:7592120}.
-!- SUBCELLULAR LOCATION: Botulinum neurotoxin A light chain: Secreted
{ECO:0000269|PubMed:6370252}. Host cytoplasm, host cytosol
{ECO:0000305|PubMed:7578132, ECO:0000305|PubMed:8243676,
ECO:0000305|PubMed:9886085}.
-!- SUBCELLULAR LOCATION: Botulinum neurotoxin A heavy chain: Secreted
{ECO:0000269|PubMed:6370252}. Host cell junction, host synapse,
host presynaptic cell membrane {ECO:0000269|PubMed:6694738,
ECO:0000305|PubMed:10413679}. Host cytoplasmic vesicle, host
secretory vesicle, host synaptic vesicle membrane
{ECO:0000269|PubMed:23471747, ECO:0000305|PubMed:10413679,
ECO:0000305|PubMed:21632541, ECO:0000305|PubMed:21832053,
ECO:0000305|PubMed:24240280, ECO:0000305|PubMed:6694738}; Multi-
pass membrane protein {ECO:0000305|PubMed:17666397,
ECO:0000305|PubMed:19096517, ECO:0000305|PubMed:2446925}.
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).
{ECO:0000269|PubMed:21632541, ECO:0000269|PubMed:21832053,
ECO:0000269|PubMed:23471747, ECO:0000269|PubMed:24240280}.
-!- INDUCTION: In cultured bacteria, first detected in late
exponential growth (17 hours), reaches maximal levels at 24-25
hours and remains nearly constant for 5 days (at protein level).
{ECO:0000269|PubMed:7592120}.
-!- DOMAIN: Botulinum neurotoxin A light chain: Has protease activity
(PubMed:7578132). {ECO:0000269|PubMed:7578132}.
-!- 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). Upon trypsin digestion the isolated TD
forms channels in bilayers when the cis side is acidic/oxidizing
and the trans side is pH 7.0/reducing (PubMed:2446925,
PubMed:17666397, PubMed:19096517). The RBD rotates 140 degrees
around the TD in the presence of NTNHA (PubMed:22363010). The 3
major domains each serve as a chaperone for the other 2 to ensure
they act only in the correct host cell context (PubMed:19096517).
In BoNT/A structures the LC is separated from the RBD by the TD;
the belt wraps around the perimeter of the LC, protecting Zn(2+)
in the active site (PubMed:18032388, PubMed:19351593,
PubMed:22363010). The belt region (449-545) may be a
pseudosubstrate inhibitor which serves as an intramolecular
chaperone for the LC prior to its translocation into the host
cytosol (PubMed:17907800). {ECO:0000269|PubMed:17666397,
ECO:0000269|PubMed:18032388, ECO:0000269|PubMed:19096517,
ECO:0000269|PubMed:19351593, ECO:0000269|PubMed:22363010,
ECO:0000269|PubMed:2446925, ECO:0000305|PubMed:17907800}.
-!- PTM: Botulinum neurotoxin A light chain: Has slow autocatalytic
activity, cleaves 250-Tyr-Tyr-251, 266-Phe-Gly-267, 419-Phe-Thr-
420, 423-Phe-Glu-424, 430-Cys-Val-431, 432-Arg-Gly-433, 438-Lys-
Thr-439, and probably 429-Leu-Cys-430 over a period of 4 weeks.
Catalysis of the '197-Gln-|-Arg-198' bond in SNAP25 is estimated
to be 10(5) more efficient than autocatalysis, leaving the
physiological importance of autocatalysis in doubt
(PubMed:11565902). {ECO:0000269|PubMed:11565902}.
-!- BIOTECHNOLOGY: Dynamin inhibitors slow toxin uptake by nerve
cells, and might be used to prolong the treatment window for
antitoxins. {ECO:0000305|PubMed:21832053}.
-!- BIOTECHNOLOGY: Replacement of the RBD by other proteins (such as
wheat germ agglutinin) allows the rest of the toxin to be taken up
by other cell types, and can be used for investigating synaptic
vesicle docking-dependent processes in BoNT resistant cells
(PubMed:10768948). LC retains protease activity (PubMed:10768948,
PubMed:19351593). {ECO:0000269|PubMed:10768948,
ECO:0000269|PubMed:19351593}.
-!- BIOTECHNOLOGY: Isolated receptor-binding domain (RBD) can be used
as a vaccine; a mutated form that is transcytosed into the general
circulation but does not enter nerve cells (Leu-1266-1267-Ser) is
as efficient as wild-type RBD (PubMed:21106906).
{ECO:0000269|PubMed:21106906}.
-!- 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. Also 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. {ECO:0000305}.
-!- 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:6370252, PubMed:2126206).
{ECO:0000269|PubMed:2126206, ECO:0000269|PubMed:6370252}.
-!- 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:0000305|PubMed:21106906}.
-!- SIMILARITY: Belongs to the peptidase M27 family. {ECO:0000305}.
-!- CAUTION: Contradictory results show that only SV2C is the
receptor; in these experiments gangliosides do not improve toxin-
coreceptor interaction (PubMed:16545378).
{ECO:0000269|PubMed:16545378}.
-!- WEB RESOURCE: Name=BOTOX product information Web site;
URL="http://www.botox.com/";
-!- WEB RESOURCE: Name=Protein Spotlight; Note=From sausages to
wrinkles - Issue 19 of February 2002;
URL="https://web.expasy.org/spotlight/back_issues/019";
-!- WEB RESOURCE: Name=BotDB - A Database Resource for Clostridial
Neurotoxins;
URL="https://botdb.abcc.ncifcrf.gov/";
-----------------------------------------------------------------------
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EMBL; X52066; CAA36289.1; -; Genomic_DNA.
EMBL; M30196; AAA23262.1; -; Genomic_DNA.
EMBL; X92973; CAA63551.1; -; Genomic_DNA.
EMBL; D67030; BAA11051.1; -; Genomic_DNA.
PIR; A35294; BTCLAB.
PDB; 1UEE; Model; -; A=2-545.
PDB; 1XTF; X-ray; 2.20 A; A/B=2-420.
PDB; 1XTG; X-ray; 2.10 A; A=2-420.
PDB; 2ILP; X-ray; 1.90 A; A/B=3-424.
PDB; 2IMA; X-ray; 1.94 A; A/B=1-424.
PDB; 2IMB; X-ray; 2.41 A; A/B=3-424.
PDB; 2IMC; X-ray; 2.00 A; A/B=3-424.
PDB; 2ISE; X-ray; 2.20 A; A/B=1-420.
PDB; 2ISG; X-ray; 2.00 A; A/B=1-420.
PDB; 2ISH; X-ray; 2.00 A; A/B=1-420.
PDB; 2VU9; X-ray; 1.60 A; A=876-1296.
PDB; 2VUA; X-ray; 1.70 A; A=876-1296.
PDB; 2W2D; X-ray; 2.59 A; A/C=3-442, B/D=447-877.
PDB; 3BOK; X-ray; 1.25 A; A=3-425.
PDB; 3BON; X-ray; 1.20 A; A=3-425.
PDB; 3BOO; X-ray; 1.40 A; A=3-425.
PDB; 3V0A; X-ray; 2.70 A; A=1-1296.
PDB; 3V0B; X-ray; 3.90 A; A=1-1296.
PDB; 3V0C; X-ray; 4.30 A; A=1-1296.
PDB; 3ZUR; X-ray; 2.71 A; A/B=3-430, A/B=454-865.
PDB; 3ZUS; X-ray; 2.95 A; A/B/C/D=3-431, A/B/C/D=454-865.
PDB; 4HEV; X-ray; 2.50 A; A/B=1-425.
PDB; 4IQP; X-ray; 2.30 A; A=871-1296.
PDB; 4JRA; X-ray; 2.30 A; A/B=871-1296.
PDB; 5JLV; X-ray; 2.00 A; A/B=872-1296.
PDB; 5JMC; X-ray; 2.64 A; A/C/E/G=872-1296.
PDB; 5MK6; X-ray; 1.45 A; A=871-1296.
PDB; 5MK7; X-ray; 1.80 A; A=871-1296.
PDB; 5TPB; X-ray; 2.60 A; A/B=876-1296.
PDB; 5TPC; X-ray; 2.00 A; A=876-1296.
PDB; 5V8P; X-ray; 2.50 A; A/B=1-424.
PDB; 5V8R; X-ray; 1.90 A; A/B=1-424.
PDB; 5V8U; X-ray; 2.05 A; A/B=1-424.
PDB; 5VGV; X-ray; 2.60 A; A=1-425.
PDB; 5VGX; X-ray; 2.15 A; A=1-425.
PDBsum; 1UEE; -.
PDBsum; 1XTF; -.
PDBsum; 1XTG; -.
PDBsum; 2ILP; -.
PDBsum; 2IMA; -.
PDBsum; 2IMB; -.
PDBsum; 2IMC; -.
PDBsum; 2ISE; -.
PDBsum; 2ISG; -.
PDBsum; 2ISH; -.
PDBsum; 2VU9; -.
PDBsum; 2VUA; -.
PDBsum; 2W2D; -.
PDBsum; 3BOK; -.
PDBsum; 3BON; -.
PDBsum; 3BOO; -.
PDBsum; 3V0A; -.
PDBsum; 3V0B; -.
PDBsum; 3V0C; -.
PDBsum; 3ZUR; -.
PDBsum; 3ZUS; -.
PDBsum; 4HEV; -.
PDBsum; 4IQP; -.
PDBsum; 4JRA; -.
PDBsum; 5JLV; -.
PDBsum; 5JMC; -.
PDBsum; 5MK6; -.
PDBsum; 5MK7; -.
PDBsum; 5TPB; -.
PDBsum; 5TPC; -.
PDBsum; 5V8P; -.
PDBsum; 5V8R; -.
PDBsum; 5V8U; -.
PDBsum; 5VGV; -.
PDBsum; 5VGX; -.
PROSITE; PS00142; ZINC_PROTEASE; 1.
1: Evidence at protein level;
3D-structure; Cell wall; Direct protein sequencing; Disulfide bond;
Host cell junction; Host cell membrane; Host cytoplasm;
Host cytoplasmic vesicle; Host membrane; Host synapse; Hydrolase;
Lipid-binding; Membrane; Metal-binding; Metalloprotease; Neurotoxin;
Pharmaceutical; Protease; Secreted; Toxin; Transmembrane;
Transmembrane helix; Virulence; Zinc.
INIT_MET 1 1 Removed. {ECO:0000269|PubMed:2126206,
ECO:0000269|PubMed:6370252,
ECO:0000269|Ref.6,
ECO:0000305|PubMed:11565902}.
CHAIN 2 1296 Botulinum neurotoxin type A.
/FTId=PRO_0000444902.
CHAIN 2 448 Botulinum neurotoxin A light chain.
{ECO:0000269|PubMed:6370252}.
/FTId=PRO_0000029211.
CHAIN 449 1296 Botulinum neurotoxin A heavy chain.
{ECO:0000269|PubMed:6370252}.
/FTId=PRO_0000029212.
TRANSMEM 627 647 Helical. {ECO:0000255}.
TRANSMEM 656 676 Helical. {ECO:0000255}.
REGION 449 870 Translocation domain (TD); not required
to bind NTNHA.
{ECO:0000269|PubMed:22363010,
ECO:0000305|PubMed:19096517}.
REGION 492 545 Belt; not required for channel formation.
{ECO:0000305|PubMed:22158863}.
REGION 871 1092 N-terminus of receptor binding domain (N-
RBD). {ECO:0000305|PubMed:19096517}.
REGION 1093 1296 C-terminus of receptor binding domain (C-
RBD). {ECO:0000305|PubMed:19096517}.
REGION 1252 1253 Interaction with host ganglioside GT1b.
{ECO:0000244|PDB:2VU9,
ECO:0000244|PDB:5TPB,
ECO:0000244|PDB:5TPC,
ECO:0000269|PubMed:18704164,
ECO:0000269|PubMed:27958736,
ECO:0000305|PubMed:14731268}.
MOTIF 1264 1267 Host ganglioside-binding motif; interacts
with GT1b. {ECO:0000244|PDB:2VU9,
ECO:0000244|PDB:5TPB,
ECO:0000244|PDB:5TPC,
ECO:0000269|PubMed:18704164,
ECO:0000269|PubMed:27958736,
ECO:0000305|PubMed:14731268,
ECO:0000305|PubMed:19650874}.
ACT_SITE 224 224 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU10095,
ECO:0000305|PubMed:10694409}.
METAL 223 223 Zinc; via tele nitrogen; catalytic.
{ECO:0000244|PDB:1XTF,
ECO:0000244|PDB:1XTG,
ECO:0000244|PDB:2W2D,
ECO:0000244|PDB:3V0A,
ECO:0000244|PDB:3V0B,
ECO:0000255|PROSITE-ProRule:PRU10095,
ECO:0000269|PubMed:15592454,
ECO:0000269|PubMed:19351593}.
METAL 227 227 Zinc; via tele nitrogen; catalytic.
{ECO:0000244|PDB:1XTF,
ECO:0000244|PDB:1XTG,
ECO:0000244|PDB:2W2D,
ECO:0000244|PDB:3V0A,
ECO:0000244|PDB:3V0B,
ECO:0000255|PROSITE-ProRule:PRU10095,
ECO:0000269|PubMed:15592454,
ECO:0000269|PubMed:19351593,
ECO:0000305|PubMed:7578132}.
METAL 262 262 Zinc; catalytic. {ECO:0000244|PDB:1XTF,
ECO:0000244|PDB:1XTG,
ECO:0000244|PDB:2W2D,
ECO:0000244|PDB:3V0A,
ECO:0000244|PDB:3V0B,
ECO:0000269|PubMed:15592454,
ECO:0000269|PubMed:19351593,
ECO:0000305|PubMed:11700044}.
BINDING 1117 1117 Host ganglioside GT1b.
{ECO:0000244|PDB:2VU9,
ECO:0000244|PDB:5TPB,
ECO:0000244|PDB:5TPC,
ECO:0000269|PubMed:18704164,
ECO:0000269|PubMed:27958736}.
BINDING 1203 1203 Host ganglioside GT1b.
{ECO:0000244|PDB:2VU9,
ECO:0000244|PDB:5TPB,
ECO:0000244|PDB:5TPC,
ECO:0000269|PubMed:18704164,
ECO:0000269|PubMed:27958736,
ECO:0000305|PubMed:14731268}.
SITE 363 363 Transition state stabilizer.
{ECO:0000305|PubMed:11827515}.
SITE 366 366 Transition state stabilizer.
{ECO:0000305|PubMed:11827515}.
DISULFID 430 454 Interchain (between light and heavy
chains). {ECO:0000244|PDB:2W2D,
ECO:0000244|PDB:3V0A,
ECO:0000244|PDB:3V0B,
ECO:0000244|PDB:3V0C,
ECO:0000269|PubMed:19351593,
ECO:0000269|PubMed:22363010,
ECO:0000305|PubMed:17666397}.
DISULFID 1235 1280 {ECO:0000244|PDB:3V0C,
ECO:0000244|PDB:5MK7}.
VARIANT 27 27 V -> A (in strain 62A).
MUTAGEN 224 224 E->D: Light chain has 5% cleavage
activity on SNAP25. KM for SNAP25 is
nearly wild-type.
{ECO:0000269|PubMed:10694409}.
MUTAGEN 224 224 E->Q: Light chain no longer cleaves
SNAP25, no effect on substrate or Zn(2+)
binding. {ECO:0000269|PubMed:10694409}.
MUTAGEN 227 227 H->Y: Light chain no longer cleaves
SNAP25, not toxic in vitro or in vivo
when reconstituted with heavy chain.
{ECO:0000269|PubMed:7578132}.
MUTAGEN 262 262 E->A: Light chain has 20% cleavage
activity on SNAP25, 40% decrease in
Zn(2+). {ECO:0000269|PubMed:11700044}.
MUTAGEN 266 266 F->A: Light chain has 50% cleavage
activity on SNAP25, no effect on Zn(2+)
binding. {ECO:0000269|PubMed:11700044}.
MUTAGEN 351 351 E->A,Q: Wild-type KM for SNAP25, no
protease activity, about 30% less Zn(2+).
{ECO:0000269|PubMed:11827515}.
MUTAGEN 363 363 R->A,H,K: Wild-type KM for SNAP25, about
75-fold decrease in kcat, no effect on
Zn(2+) binding.
{ECO:0000269|PubMed:11827515}.
MUTAGEN 366 366 Y->A: Light chain has 40% cleavage
activity on SNAP25, 30% decrease in
Zn(2+). {ECO:0000269|PubMed:11700044}.
MUTAGEN 366 366 Y->F: About wild-type KM for SNAP25, 35-
fold decrease in kcat, no effect on
Zn(2+) binding.
{ECO:0000269|PubMed:11827515}.
MUTAGEN 861 871 RLLSTFTEYIK->ALLSTFTPYIP: Reduced
toxicity. {ECO:0000269|PubMed:22363010}.
MUTAGEN 862 867 LLSTFT->KESTFK: Reduced toxicity.
{ECO:0000269|PubMed:22363010}.
MUTAGEN 953 953 F->G: Whole toxin has 50-fold reduction
in toxicity, almost no binding of RBD to
neurons. {ECO:0000269|PubMed:27294781}.
MUTAGEN 953 953 F->R: Whole toxin is non-toxic, almost no
binding of RBD to neurons.
{ECO:0000269|PubMed:27294781}.
MUTAGEN 982 982 E->A,Q: Decreased binding of NTNHA by
receptor-binding domain (RBD) at pH 7.5.
{ECO:0000269|PubMed:22363010}.
MUTAGEN 1000 1000 K->A: Decreased binding of NTNHA by RBD
at pH 6.0, none at pH 7.5.
{ECO:0000269|PubMed:22363010}.
MUTAGEN 1037 1037 D->A,N: Decreased binding of NTNHA by RBD
at pH 7.5. {ECO:0000269|PubMed:22363010}.
MUTAGEN 1064 1064 H->G,R: Whole toxin has reduced toxicity,
dramatically reduced binding of RBD to
neurons. {ECO:0000269|PubMed:27294781}.
MUTAGEN 1118 1118 D->A: Decreased binding of NTNHA by RBD
at pH 7.5. {ECO:0000269|PubMed:22363010}.
MUTAGEN 1145 1146 TT->AA: No binding of RBD to neurons.
Loss of binding to SV2C.
{ECO:0000269|PubMed:24240280,
ECO:0000269|PubMed:27294781}.
MUTAGEN 1156 1156 R->E: Decreased binding of RBD to SV2C,
substantial binding to neurons.
{ECO:0000269|PubMed:24240280,
ECO:0000269|PubMed:27294781}.
MUTAGEN 1171 1171 D->A: Decreased binding of NTNHA by RBD
at pH 7.5. {ECO:0000269|PubMed:22363010}.
MUTAGEN 1203 1203 E->L: Strongly reduced toxicity, heavy
chain has very strongly reduced binding
to synaptosomes, decreased binding to
gangioside GT1b.
{ECO:0000269|PubMed:14731268}.
MUTAGEN 1253 1253 H->A: Strongly reduced toxicity, heavy
chain has very strongly reduced binding
to synaptosomes, decrease in ganglioside
GT1b binding.
{ECO:0000269|PubMed:14731268}.
MUTAGEN 1253 1253 H->W: Heavy chain has very strongly
reduced binding to synaptosomes, binds
much less GT1b. RBD protects against
neurotoxin less well than wild-type.
{ECO:0000269|PubMed:14731268,
ECO:0000269|PubMed:21106906}.
MUTAGEN 1264 1264 S->A: Reduced toxicity, heavy chain has
strongly reduced binding to synaptosomes,
heavy chain binds less GT1b.
{ECO:0000269|PubMed:14731268}.
MUTAGEN 1266 1267 WY->LS: Whole RBD does not protect
against neurotoxin, no effect on
epithelial cell passage; can be used as a
vaccine. {ECO:0000269|PubMed:21106906}.
MUTAGEN 1266 1266 W->L: Nearly complete loss of toxicity,
heavy chain has very strongly reduced
binding to synaptosomes, binds much less
GT1b. Heavy chain no longer inhibits
whole-toxin uptake and toxicity. RBD
protects against neurotoxin considerably
less well than wild-type.
{ECO:0000269|PubMed:14731268,
ECO:0000269|PubMed:19650874,
ECO:0000269|PubMed:21106906}.
MUTAGEN 1267 1267 Y->F: Nearly complete loss of toxicity,
heavy chain has very strongly reduced
binding to synaptosomes, binds much less
GT1b. {ECO:0000269|PubMed:14731268}.
MUTAGEN 1267 1267 Y->S: Nearly complete loss of toxicity,
heavy chain has very strongly reduced
binding to synaptosomes, binds much less
GT1b. RBD protects against neurotoxin
considerably less well than wild-type.
{ECO:0000269|PubMed:14731268,
ECO:0000269|PubMed:21106906}.
MUTAGEN 1292 1292 G->Q: Whole toxin has very strongly
reduced toxicity, almost no binding of
RBD to neurons.
{ECO:0000269|PubMed:27294781}.
MUTAGEN 1292 1292 G->R: Nearly complete loss of toxicity,
almost no binding of RBD to neurons.
{ECO:0000269|PubMed:27294781}.
MUTAGEN 1294 1294 R->A: Decreased binding of RBD to SV2C,
substantial binding to neurons.
{ECO:0000269|PubMed:24240280}.
MUTAGEN 1294 1294 R->S: Decreased binding of RBD to SV2C,
substantial binding to neurons.
{ECO:0000269|PubMed:27294781}.
CONFLICT 2 2 P -> Q (in Ref. 1; CAA36289).
{ECO:0000305}.
CONFLICT 480 480 E -> P (in Ref. 9; AA sequence).
{ECO:0000305}.
SEQUENCE 1296 AA; 149454 MW; B731EF5BA5E62FDA CRC64;
MPFVNKQFNY KDPVNGVDIA YIKIPNVGQM QPVKAFKIHN KIWVIPERDT FTNPEEGDLN
PPPEAKQVPV SYYDSTYLST DNEKDNYLKG VTKLFERIYS TDLGRMLLTS IVRGIPFWGG
STIDTELKVI DTNCINVIQP DGSYRSEELN LVIIGPSADI IQFECKSFGH EVLNLTRNGY
GSTQYIRFSP DFTFGFEESL EVDTNPLLGA GKFATDPAVT LAHELIHAGH RLYGIAINPN
RVFKVNTNAY YEMSGLEVSF EELRTFGGHD AKFIDSLQEN EFRLYYYNKF KDIASTLNKA
KSIVGTTASL QYMKNVFKEK YLLSEDTSGK FSVDKLKFDK LYKMLTEIYT EDNFVKFFKV
LNRKTYLNFD KAVFKINIVP KVNYTIYDGF NLRNTNLAAN FNGQNTEINN MNFTKLKNFT
GLFEFYKLLC VRGIITSKTK SLDKGYNKAL NDLCIKVNNW DLFFSPSEDN FTNDLNKGEE
ITSDTNIEAA EENISLDLIQ QYYLTFNFDN EPENISIENL SSDIIGQLEL MPNIERFPNG
KKYELDKYTM FHYLRAQEFE HGKSRIALTN SVNEALLNPS RVYTFFSSDY VKKVNKATEA
AMFLGWVEQL VYDFTDETSE VSTTDKIADI TIIIPYIGPA LNIGNMLYKD DFVGALIFSG
AVILLEFIPE IAIPVLGTFA LVSYIANKVL TVQTIDNALS KRNEKWDEVY KYIVTNWLAK
VNTQIDLIRK KMKEALENQA EATKAIINYQ YNQYTEEEKN NINFNIDDLS SKLNESINKA
MININKFLNQ CSVSYLMNSM IPYGVKRLED FDASLKDALL KYIYDNRGTL IGQVDRLKDK
VNNTLSTDIP FQLSKYVDNQ RLLSTFTEYI KNIINTSILN LRYESNHLID LSRYASKINI
GSKVNFDPID KNQIQLFNLE SSKIEVILKN AIVYNSMYEN FSTSFWIRIP KYFNSISLNN
EYTIINCMEN NSGWKVSLNY GEIIWTLQDT QEIKQRVVFK YSQMINISDY INRWIFVTIT
NNRLNNSKIY INGRLIDQKP ISNLGNIHAS NNIMFKLDGC RDTHRYIWIK YFNLFDKELN
EKEIKDLYDN QSNSGILKDF WGDYLQYDKP YYMLNLYDPN KYVDVNNVGI RGYMYLKGPR
GSVMTTNIYL NSSLYRGTKF IIKKYASGNK DNIVRNNDRV YINVVVKNKE YRLATNASQA
GVEKILSALE IPDVGNLSQV VVMKSKNDQG ITNKCKMNLQ DNNGNDIGFI GFHQFNNIAK
LVASNWYNRQ IERSSRTLGC SWEFIPVDDG WGERPL


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