BXC_CBCP
ID BXC_CBCP Reviewed; 1291 AA.
AC P18640;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 18-JUL-2018, sequence version 3.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Botulinum neurotoxin type C;
DE Short=BoNT/C;
DE AltName: Full=Bontoxilysin-C1;
DE Short=BoNT/C1 {ECO:0000303|PubMed:2204031};
DE AltName: Full=Botulinum neurotoxin type C1;
DE Contains:
DE RecName: Full=Botulinum neurotoxin C light chain;
DE Short=LC;
DE EC=3.4.24.69 {ECO:0000269|PubMed:7737992};
DE Contains:
DE RecName: Full=Botulinum neurotoxin C heavy chain;
DE Short=HC;
DE Flags: Precursor;
OS Clostridium botulinum C phage (Clostridium botulinum C bacteriophage).
OC Viruses; Duplodnaviria; Heunggongvirae; Uroviricota; Caudoviricetes;
OC Caudovirales; Siphoviridae.
OX NCBI_TaxID=12336;
OH NCBI_TaxID=36828; Clostridium botulinum C.
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=468C / phage c-st / Type C1;
RX PubMed=2204031; DOI=10.1093/nar/18.16.4924;
RA Hauser D., Eklund M.W., Kurazona H., Binz T., Niemann H., Gill D.M.,
RA Boquet P., Popoff M.R.;
RT "Nucleotide sequence of Clostridium botulinum C1 neurotoxin.";
RL Nucleic Acids Res. 18:4924-4924(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Stockholm / Type C / phage C-ST;
RX PubMed=2222445; DOI=10.1016/0006-291x(90)90828-b;
RA Kimura K., Fujii N., Tsuzuki K., Murakami T., Indoh T., Yokosawa N.,
RA Takeshi K., Syuto B., Oguma K.;
RT "The complete nucleotide sequence of the gene coding for botulinum type C1
RT toxin in the C-ST phage genome.";
RL Biochem. Biophys. Res. Commun. 171:1304-1311(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION (BOTULINUM NEUROTOXIN TYPE C),
RP EUKARYOTIC HOST RANGE, SUBUNIT, AND SUBCELLULAR LOCATION (BOTULINUM
RP NEUROTOXIN C LIGHT CHAIN AND BOTULINUM NEUROTOXIN C HEAVY CHAIN).
RC STRAIN=CB-19 / Type C;
RX PubMed=16252491; DOI=10.1637/7347-022305r1.1;
RA Takeda M., Tsukamoto K., Kohda T., Matsui M., Mukamoto M., Kozaki S.;
RT "Characterization of the neurotoxin produced by isolates associated with
RT avian botulism.";
RL Avian Dis. 49:376-381(2005).
RN [4]
RP PROTEIN SEQUENCE OF 2-26.
RC STRAIN=Stockholm / Type C;
RX PubMed=2450068; DOI=10.1128/iai.56.4.898-902.1988;
RA Tsuzuki K., Yokosawa N., Syuto B., Ohishi I., Fujii N., Kimura K.,
RA Oguma K.;
RT "Establishment of a monoclonal antibody recognizing an antigenic site
RT common to Clostridium botulinum type B, C1, D, and E toxins and tetanus
RT toxin.";
RL Infect. Immun. 56:898-902(1988).
RN [5]
RP FUNCTION (BOTULINUM NEUROTOXIN TYPE C).
RC STRAIN=Type C;
RX PubMed=2424493; DOI=10.1021/bi00358a020;
RA Donovan J.J., Middlebrook J.L.;
RT "Ion-conducting channels produced by botulinum toxin in planar lipid
RT membranes.";
RL Biochemistry 25:2872-2876(1986).
RN [6]
RP EUKARYOTIC HOST RANGE.
RC STRAIN=Type C;
RX PubMed=1978909; DOI=10.1016/0140-6736(90)93157-k;
RA Oguma K., Yokota K., Hayashi S., Takeshi K., Kumagai M., Itoh N., Tachi N.,
RA Chiba S.;
RT "Infant botulism due to Clostridium botulinum type C toxin.";
RL Lancet 336:1449-1450(1990).
RN [7]
RP FUNCTION (BOTULINUM NEUROTOXIN TYPE C), IDENTIFICATION OF SUBSTRATE,
RP ACTIVITY REGULATION, AND SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN C LIGHT
RP CHAIN).
RX PubMed=7901002; DOI=10.1002/j.1460-2075.1993.tb06171.x;
RA Blasi J., Chapman E.R., Yamasaki S., Binz T., Niemann H., Jahn R.;
RT "Botulinum neurotoxin C1 blocks neurotransmitter release by means of
RT cleaving HPC-1/syntaxin.";
RL EMBO J. 12:4821-4828(1993).
RN [8]
RP SUBUNIT, AND SUBCELLULAR LOCATION (BOTULINUM NEUROTOXIN C LIGHT CHAIN AND
RP BOTULINUM NEUROTOXIN C HEAVY CHAIN).
RC STRAIN=Stockholm / Type C / phage C-ST;
RX PubMed=7802661; DOI=10.1006/bbrc.1994.2805;
RA Fujinaga Y., Inoue K., Shimazaki S., Tomochika K., Tsuzuki K., Fujii N.,
RA Watanabe T., Ohyama T., Takeshi K., Inoue K., Oguma K.;
RT "Molecular construction of Clostridium botulinum type C progenitor toxin
RT and its gene organization.";
RL Biochem. Biophys. Res. Commun. 205:1291-1298(1994).
RN [9]
RP FUNCTION (BOTULINUM NEUROTOXIN C LIGHT CHAIN), IDENTIFICATION OF SUBSTRATE,
RP CATALYTIC ACTIVITY, COFACTOR, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION
RP (BOTULINUM NEUROTOXIN C LIGHT CHAIN).
RC STRAIN=NCTC 8264 / Type C;
RX PubMed=7737992; DOI=10.1074/jbc.270.18.10566;
RA Schiavo G., Shone C.C., Bennett M.K., Scheller R.H., Montecucco C.;
RT "Botulinum neurotoxin type C cleaves a single Lys-Ala bond within the
RT carboxyl-terminal region of syntaxins.";
RL J. Biol. Chem. 270:10566-10570(1995).
RN [10]
RP FUNCTION (BOTULINUM NEUROTOXIN TYPE C), IDENTIFICATION OF SUBSTRATE,
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RC STRAIN=Type C1;
RX PubMed=8611567; DOI=10.1021/bi9519009;
RA Foran P., Lawrence G.W., Shone C.C., Foster K.A., Dolly J.O.;
RT "Botulinum neurotoxin C1 cleaves both syntaxin and SNAP-25 in intact and
RT permeabilized chromaffin cells: correlation with its blockade of
RT catecholamine release.";
RL Biochemistry 35:2630-2636(1996).
RN [11]
RP PHARMACEUTICAL.
RX PubMed=9086464; DOI=10.1016/s0304-3940(97)13448-6;
RA Eleopra R., Tugnoli V., Rossetto O., Montecucco C., De Grandis D.;
RT "Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy
RT in human.";
RL Neurosci. Lett. 224:91-94(1997).
RN [12]
RP FUNCTION (BOTULINUM NEUROTOXIN C LIGHT CHAIN), IDENTIFICATION OF SUBSTRATE,
RP AND CATALYTIC ACTIVITY.
RC STRAIN=Type C;
RX PubMed=9886085; DOI=10.1046/j.1471-4159.1999.0720327.x;
RA Vaidyanathan V.V., Yoshino K., Jahnz M., Doerries C., Bade S.,
RA Nauenburg S., Niemann H., Binz T.;
RT "Proteolysis of SNAP-25 isoforms by botulinum neurotoxin types A, C, and E:
RT domains and amino acid residues controlling the formation of enzyme-
RT substrate complexes and cleavage.";
RL J. Neurochem. 72:327-337(1999).
RN [13]
RP FUNCTION (BOTULINUM NEUROTOXIN C HEAVY CHAIN), AND GANGLIOSIDE-BINDING.
RC STRAIN=CB-19 / Type C;
RX PubMed=16115873; DOI=10.1074/jbc.m507596200;
RA Tsukamoto K., Kohda T., Mukamoto M., Takeuchi K., Ihara H., Saito M.,
RA Kozaki S.;
RT "Binding of Clostridium botulinum type C and D neurotoxins to ganglioside
RT and phospholipid. Novel insights into the receptor for clostridial
RT neurotoxins.";
RL J. Biol. Chem. 280:35164-35171(2005).
RN [14]
RP FUNCTION (BOTULINUM NEUROTOXIN TYPE C), FUNCTION (BOTULINUM NEUROTOXIN C
RP HEAVY CHAIN), GANGLIOSIDE-BINDING, AND MUTAGENESIS OF TRP-1258.
RC STRAIN=468C / phage c-st / Type C1;
RX PubMed=19650874; DOI=10.1111/j.1471-4159.2009.06298.x;
RA Rummel A., Haefner K., Mahrhold S., Darashchonak N., Holt M., Jahn R.,
RA Beermann S., Karnath T., Bigalke H., Binz T.;
RT "Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding
RT site prior to stimulation-dependent uptake with botulinum neurotoxin F
RT utilising the three isoforms of SV2 as second receptor.";
RL J. Neurochem. 110:1942-1954(2009).
RN [15]
RP FUNCTION (BOTULINUM NEUROTOXIN TYPE C), AND POSSIBLE LACK OF PROTEINACEOUS
RP RECEPTOR.
RC STRAIN=Type C;
RX PubMed=21483489; DOI=10.1371/journal.ppat.1002008;
RA Peng L., Tepp W.H., Johnson E.A., Dong M.;
RT "Botulinum neurotoxin D uses synaptic vesicle protein SV2 and gangliosides
RT as receptors.";
RL PLoS Pathog. 7:E1002008-E1002008(2011).
RN [16]
RP FUNCTION (BOTULINUM NEUROTOXIN C HEAVY CHAIN), DOMAIN, AND
RP PHOSPHOINOSITIDE-BINDING.
RX PubMed=22120109; DOI=10.1016/j.biochi.2011.11.004;
RA Zhang Y., Varnum S.M.;
RT "The receptor binding domain of botulinum neurotoxin serotype C binds
RT phosphoinositides.";
RL Biochimie 94:920-923(2012).
RN [17]
RP FUNCTION (BOTULINUM NEUROTOXIN C HEAVY CHAIN), SUBCELLULAR LOCATION
RP (BOTULINUM NEUROTOXIN C HEAVY CHAIN), GANGLIOSIDE-BINDING, AND MUTAGENESIS
RP OF TYR-1119; ALA-1126 AND HIS-1193.
RC STRAIN=Stockholm / Type C;
RX PubMed=23027864; DOI=10.1074/jbc.m112.404244;
RA Karalewitz A.P., Fu Z., Baldwin M.R., Kim J.J., Barbieri J.T.;
RT "Botulinum neurotoxin serotype C associates with dual ganglioside receptors
RT to facilitate cell entry.";
RL J. Biol. Chem. 287:40806-40816(2012).
RN [18]
RP REVIEW.
RX PubMed=28356439; DOI=10.1124/pr.116.012658;
RA Pirazzini M., Rossetto O., Eleopra R., Montecucco C.;
RT "Botulinum neurotoxins: Biology, pharmacology, and toxicology.";
RL Pharmacol. Rev. 69:200-235(2017).
RN [19] {ECO:0007744|PDB:2QN0}
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 1-427 IN COMPLEX WITH ZINC,
RP FUNCTION (BOTULINUM NEUROTOXIN C LIGHT CHAIN), COFACTOR, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RC STRAIN=Type C;
RX PubMed=17718519; DOI=10.1021/bi701162d;
RA Jin R., Sikorra S., Stegmann C.M., Pich A., Binz T., Brunger A.T.;
RT "Structural and biochemical studies of botulinum neurotoxin serotype C1
RT light chain protease: implications for dual substrate specificity.";
RL Biochemistry 46:10685-10693(2007).
RN [20] {ECO:0007744|PDB:3DEB}
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 1-430 IN APO-FORM.
RC STRAIN=Type C;
RA Rawat R., Kumaran D., Swaminathan S.;
RT "Crystal structure of apo form (zinc removed) of the botulinum neurotoxin
RT type C light chain.";
RL Submitted (JUN-2008) to the PDB data bank.
RN [21] {ECO:0007744|PDB:3N7K}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 866-1291, FUNCTION (BOTULINUM
RP NEUROTOXIN C HEAVY CHAIN), DOMAIN, GANGLIOSIDE-BINDING, AND MUTAGENESIS OF
RP TRP-1258.
RC STRAIN=Type C / Stockholm / phage C-ST;
RX PubMed=20731382; DOI=10.1021/bi100865f;
RA Karalewitz A.P., Kroken A.R., Fu Z., Baldwin M.R., Kim J.J., Barbieri J.T.;
RT "Identification of a unique ganglioside binding loop within botulinum
RT neurotoxins C and D-SA.";
RL Biochemistry 49:8117-8126(2010).
RN [22] {ECO:0007744|PDB:3R4S, ECO:0007744|PDB:3R4U}
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 867-1291 WITH AND WITHOUT SIALIC
RP ACID, FUNCTION (BOTULINUM NEUROTOXIN C HEAVY CHAIN), AND MUTAGENESIS OF
RP TYR-1146; TYR-1179; LEU-1203; 1258-TRP-TYR-1259; TRP-1258 AND SER-1281.
RX PubMed=21542861; DOI=10.1111/j.1365-2958.2011.07682.x;
RA Strotmeier J., Gu S., Jutzi S., Mahrhold S., Zhou J., Pich A., Eichner T.,
RA Bigalke H., Rummel A., Jin R., Binz T.;
RT "The biological activity of botulinum neurotoxin type C is dependent upon
RT novel types of ganglioside binding sites.";
RL Mol. Microbiol. 81:143-156(2011).
CC -!- FUNCTION: [Botulinum neurotoxin type C]: Botulinum toxin causes flaccid
CC paralysis by inhibiting neurotransmitter (acetylcholine) release from
CC the presynaptic membranes of nerve terminals of the eukaryotic host
CC skeletal and autonomic nervous system, with frequent heart or
CC respiratory failure (PubMed:16252491, PubMed:7901002, PubMed:8611567).
CC Is unique among characterized BoNTs in having 2 substrates, syntaxin
CC (STX) and SNAP25 (PubMed:7901002, PubMed:7737992, PubMed:8611567,
CC PubMed:9886085, PubMed:17718519). Precursor of botulinum neurotoxin C
CC which unlike most BoNTs seems not to have a proteinaceous coreceptor,
CC and instead recognizes 2 different complex polysialylated gangliosides
CC found on neural tissue probably found in synaptic vesicles
CC (PubMed:21483489, PubMed:23027864). Upon synaptic vesicle recycling the
CC toxin is taken up via the endocytic pathway. When the pH of the toxin-
CC containing endosome drops a structural rearrangement occurs so that the
CC N-terminus of the heavy chain (HC) forms pores that allows the light
CC chain (LC) to translocate into the cytosol (By similarity). Once in the
CC cytosol the disulfide bond linking the 2 subunits is reduced and LC
CC cleaves its target protein on synaptic vesicles, preventing their
CC fusion with the cytoplasmic membrane and thus neurotransmitter release
CC (By similarity). In vitro the whole toxin only has protease activity
CC after reduction (PubMed:8611567). Electrical stimulation increases
CC uptake of toxin, presumably by transiently exposing a receptor usually
CC found in eukaryotic target synaptic vesicles (PubMed:19650874). Forms
CC ion-conducting channels at around pH 6.1 (PubMed:2424493). Requires
CC complex eukaryotic host polysialogangliosides for full neurotoxicity
CC (PubMed:19650874, PubMed:21483489). Synaptic vesicle glycoproteins
CC (SV2) do not seem to act as its receptor (PubMed:21483489).
CC {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:17718519,
CC ECO:0000269|PubMed:19650874, ECO:0000269|PubMed:21483489,
CC ECO:0000269|PubMed:2424493, ECO:0000269|PubMed:7737992,
CC ECO:0000269|PubMed:7901002, ECO:0000269|PubMed:8611567,
CC ECO:0000269|PubMed:9886085, ECO:0000305|PubMed:16252491,
CC ECO:0000305|PubMed:23027864}.
CC -!- FUNCTION: [Botulinum neurotoxin C light chain]: Has proteolytic
CC activity. After translocation into the eukaryotic host cytosol,
CC inhibits neurotransmitter release by acting as a zinc endopeptidase
CC that cleaves syntaxin-1A/STX1A and syntaxin-1B/STX1B (PubMed:7901002,
CC PubMed:7737992, PubMed:8611567). Cleaves the '253-Arg-|-Ala-254' bond
CC of STX1 and the '252-Arg-|-Ala-253' bond of STX2; also acts on syntaxin
CC 3 (STX3) but not 4 (STX4) (PubMed:7737992). Cleaves the '198-Arg-|-Ala-
CC 199' bond of SNAP25 (PubMed:8611567, PubMed:9886085, PubMed:17718519).
CC Recognizes the '93-Asn--Met-202' region of SNAP25 (PubMed:9886085).
CC {ECO:0000269|PubMed:17718519, ECO:0000269|PubMed:7737992,
CC ECO:0000269|PubMed:7901002, ECO:0000269|PubMed:8611567,
CC ECO:0000269|PubMed:9886085}.
CC -!- FUNCTION: [Botulinum neurotoxin C heavy chain]: Responsible for host
CC epithelial cell transcytosis, host nerve cell targeting and
CC translocation of light chain (LC) into eukaryotic host cytosol.
CC Composed of 3 subdomains; the translocation domain (TD), and N-terminus
CC and C-terminus of the receptor-binding domain (RBD). The RBD is
CC responsible for the adherence of the toxin to the eukaryotic target
CC cell surface. It simultaneously recognizes 2 polysialated gangliosides
CC coreceptors in close proximity on host synaptic vesicles
CC (PubMed:23027864, PubMed:21542861). The N-terminus of the TD wraps an
CC extended belt around the perimeter of the LC, protecting Zn(2+) in the
CC active site; it may also prevent premature LC dissociation from the
CC translocation channel and protect toxin prior to translocation (By
CC similarity). The TD inserts into synaptic vesicle membrane to allow
CC translocation into the host cytosol (Probable). The C-terminal half of
CC the HC (residues 864-1291) binds neurons in a dose-dependent manner
CC (PubMed:20731382). The C-terminal half of the HC (residues 863-1291)
CC binds eukaryotic host gangliosides in the order GD1b > GT1b > GD1a >
CC GM1a (PubMed:16115873, PubMed:20731382, PubMed:23027864,
CC PubMed:19650874). Has 2 ganglioside binding sites; Sia-1 prefers a sia7
CC sialic acid and sugars within the ganglioside (GD1b > GT1b), whereas
CC GBP2 recognizes a sia5 sialic acid (GT1b and GD1a) (PubMed:23027864,
CC PubMed:21542861). Both sites are required for HC to enter neurons,
CC acting via different gangliosides (PubMed:23027864). This suggests that
CC 2 gangliosides serve as toxin receptors (PubMed:16115873,
CC PubMed:20731382, PubMed:21542861, PubMed:23027864). Synaptic activity
CC (depolarization with K(+)) increases uptake by neurons
CC (PubMed:23027864). Treatment of synaptosomes with proteinase K does not
CC reduce HC binding, suggesting there is no protein receptor or it is
CC protected from extracellular proteases (PubMed:16115873). Decreases
CC uptake and toxicity of whole BoNT/A, but also interferes with uptake of
CC BoNT/E and BoNT/F (PubMed:19650874). HC also binds phosphoinositides,
CC which might play a role in membrane-binding (PubMed:22120109).
CC {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:16115873,
CC ECO:0000269|PubMed:19650874, ECO:0000269|PubMed:20731382,
CC ECO:0000269|PubMed:21542861, ECO:0000269|PubMed:22120109,
CC ECO:0000269|PubMed:23027864, ECO:0000305|PubMed:2424493}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Limited hydrolysis of proteins of the neuroexocytosis
CC apparatus, synaptobrevins, SNAP25 or syntaxin. No detected action on
CC small molecule substrates.; EC=3.4.24.69;
CC Evidence={ECO:0000269|PubMed:7737992, ECO:0000269|PubMed:8611567,
CC ECO:0000269|PubMed:9886085};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:17718519, ECO:0000269|PubMed:7737992};
CC Note=Binds 2 zinc ions per subunit (PubMed:7737992). The catalytic
CC Zn(2+) is bound by LC, the other Zn(2+) must bind to another region
CC (PubMed:17718519). {ECO:0000269|PubMed:17718519,
CC ECO:0000269|PubMed:7737992};
CC -!- ACTIVITY REGULATION: 1,10-phenanthroline, EDTA and partially captopril
CC block cleavage of syntaxin in brain synaptosomes (PubMed:7901002,
CC PubMed:7737992). Treatment of synaptosomes with a mild detergent also
CC inhibits cleavage (PubMed:7737992). 1,10-phenanthroline partially
CC antagonizes inhibitions of neurotransmitter release (PubMed:8611567).
CC {ECO:0000269|PubMed:7737992, ECO:0000269|PubMed:7901002,
CC ECO:0000269|PubMed:8611567}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=18.6 uM for purified SNAP25 with isolated botulinum neurotoxin C
CC light chain {ECO:0000269|PubMed:17718519};
CC Note=kcat is 0.391 min(-1), for isolated botulinum neurotoxin C light
CC chain. {ECO:0000269|PubMed:17718519};
CC -!- SUBUNIT: Heterodimer; disulfide-linked heterodimer of a light chain
CC (LC) and a heavy chain (HC) (PubMed:16252491). The LC has the
CC proteolytic/pharmacological activity (PubMed:7901002, PubMed:7737992,
CC PubMed:8611567). The N- and C-terminal of the HC mediate channel
CC formation and toxin binding, respectively. Can also be purified in
CC complex with a non-toxic component that is larger than the HC
CC (PubMed:16252491, PubMed:7802661). The stoichiometry of the whole
CC complex has been modeled as one BoNT/C, one NTNHA, three HA-70, six HA-
CC 33 and three HA-17 (By similarity). {ECO:0000250|UniProtKB:P19321,
CC ECO:0000269|PubMed:16252491, ECO:0000269|PubMed:7737992,
CC ECO:0000269|PubMed:7802661, ECO:0000269|PubMed:7901002,
CC ECO:0000269|PubMed:8611567}.
CC -!- SUBCELLULAR LOCATION: [Botulinum neurotoxin type C]: Secreted
CC {ECO:0000269|PubMed:16252491}.
CC -!- SUBCELLULAR LOCATION: [Botulinum neurotoxin C light chain]: Secreted
CC {ECO:0000269|PubMed:16252491, ECO:0000269|PubMed:7802661}. Note=In
CC animals that have ingested BoNT/C the LC acts in the eukaryotic host
CC cytosol (PubMed:7901002, PubMed:7737992, PubMed:8611567,
CC PubMed:9886085, PubMed:17718519). {ECO:0000305|PubMed:17718519,
CC ECO:0000305|PubMed:7737992, ECO:0000305|PubMed:7901002,
CC ECO:0000305|PubMed:8611567, ECO:0000305|PubMed:9886085}.
CC -!- SUBCELLULAR LOCATION: [Botulinum neurotoxin C heavy chain]: Secreted
CC {ECO:0000269|PubMed:16252491, ECO:0000269|PubMed:7802661}. Note=Upon
CC incubation with cultured neurons the HC is detected in a synaptophysin-
CC positive intracellular compartment (probably host synaptic vesicles)
CC (PubMed:23027864). It probably integrates into the eukaryotic host
CC synaptic vesicle membrane (PubMed:2424493).
CC {ECO:0000269|PubMed:23027864, ECO:0000305|PubMed:2424493}.
CC -!- DOMAIN: [Botulinum neurotoxin C light chain]: Has proteolytic activity
CC (PubMed:7901002, PubMed:7737992, PubMed:8611567, PubMed:9886085,
CC PubMed:17718519). {ECO:0000269|PubMed:17718519,
CC ECO:0000269|PubMed:7737992, ECO:0000269|PubMed:7901002,
CC ECO:0000269|PubMed:8611567, ECO:0000269|PubMed:9886085}.
CC -!- DOMAIN: [Botulinum neurotoxin C heavy chain]: Has 3 functional domains;
CC the translocation domain (TD) and the receptor-binding domain (RBD)
CC which is further subdivided into N- and C-terminal domains (N-RBD and
CC C-RBD). The N-terminus of the TD wraps an extended belt around the
CC perimeter of the LC, protecting Zn(2+) in the active site and may be a
CC pseudosubstrate inhibitor which serves as an intramolecular chaperone
CC for the LC prior to its translocation into the host cytosol. The RBD
CC binds transiently exposed coreceptors on the host presynaptic cell
CC membrane (By similarity). Binds phosphoinositides, which might play a
CC role in membrane-binding (PubMed:22120109).
CC {ECO:0000250|UniProtKB:P0DPI0, ECO:0000269|PubMed:22120109}.
CC -!- PHARMACEUTICAL: Has been used to treat human idiopathic facial
CC hemispasm and blepharospasm; improvement is seen in 2-3 days and the
CC effects last up to 12-13 weeks, making it a viable option in BoNT/A
CC non-responders (PubMed:9086464). {ECO:0000269|PubMed:9086464}.
CC -!- MISCELLANEOUS: There are seven antigenically distinct forms of
CC botulinum neurotoxin: Types A, B, C, D, E, F, and G; new subtypes are
CC quite frequent. Types C and D can undergo domain swapping to create
CC hybrid types.
CC -!- MISCELLANEOUS: Botulism poisoning is usually food-borne, either by
CC ingesting toxin or bacterial-contaminated food, or less frequently by
CC inhalation poisoning. In both cases the neurotoxin binds to the apical
CC surface of epithelial cells in the gut or airway. Toxin undergoes
CC receptor-mediated endocytosis (using a different receptor than on
CC target nerve cells), transcytosis across the epithelial cells and
CC release into the general circulation. Once in the general circulation
CC it binds to its target cells. {ECO:0000250|UniProtKB:P0DPI0}.
CC -!- MISCELLANEOUS: Botulinum neurotoxin type C is synthesized by C strains
CC of C.botulinum which carry the appropriate bacteriophage.
CC {ECO:0000305|PubMed:20731382, ECO:0000305|PubMed:2204031,
CC ECO:0000305|PubMed:2222445, ECO:0000305|PubMed:9886085}.
CC -!- MISCELLANEOUS: Strain CB-19 was isolated from mink (PubMed:16252491).
CC BoNT/C usually causes animal and avian botulism; it is less toxic to
CC chicken than is BoNT/CD (PubMed:16115873). One case of human infant
CC botulism caused by this serotype is known (PubMed:1978909).
CC {ECO:0000269|PubMed:16252491, ECO:0000269|PubMed:1978909,
CC ECO:0000305|PubMed:16115873}.
CC -!- MISCELLANEOUS: This protein can also be encoded on a prophage.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase M27 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=BotDB - A Database Resource for Clostridial
CC Neurotoxins;
CC URL="https://botdb.abcc.ncifcrf.gov/";
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DR EMBL; X66433; CAA47060.1; -; Genomic_DNA.
DR EMBL; X72793; CAA51313.1; -; Genomic_DNA.
DR EMBL; X53751; CAA37780.1; -; Genomic_DNA.
DR EMBL; D90210; BAA14235.1; -; Genomic_DNA.
DR EMBL; X62389; CAA44263.1; -; Genomic_DNA.
DR EMBL; AB200358; BAD90566.1; -; Genomic_DNA.
DR RefSeq; YP_398516.1; NC_007581.1.
DR PDB; 2QN0; X-ray; 1.75 A; A=1-427.
DR PDB; 3DEB; X-ray; 1.95 A; A=1-430.
DR PDB; 3N7K; X-ray; 2.50 A; A/B=866-1291.
DR PDB; 3R4S; X-ray; 2.15 A; A/B=867-1291.
DR PDB; 3R4U; X-ray; 2.20 A; A/B=867-1291.
DR PDBsum; 2QN0; -.
DR PDBsum; 3DEB; -.
DR PDBsum; 3N7K; -.
DR PDBsum; 3R4S; -.
DR PDBsum; 3R4U; -.
DR SMR; P18640; -.
DR DrugBank; DB13898; Equine Botulinum Neurotoxin C Immune FAB2.
DR UniLectin; P18640; -.
DR GeneID; 3772941; -.
DR KEGG; vg:3772941; -.
DR BRENDA; 3.4.24.69; 1462.
DR Reactome; R-HSA-5250971; Toxicity of botulinum toxin type C (botC).
DR EvolutionaryTrace; P18640; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0035594; F:ganglioside binding; IDA:UniProtKB.
DR GO; GO:0004222; F:metalloendopeptidase activity; IEA:UniProtKB-EC.
DR GO; GO:0008320; F:protein transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0033619; P:membrane protein proteolysis; IDA:CACAO.
DR GO; GO:0045955; P:negative regulation of calcium ion-dependent exocytosis; IDA:CACAO.
DR GO; GO:0046929; P:negative regulation of neurotransmitter secretion; IDA:UniProtKB.
DR Gene3D; 1.20.1120.10; -; 1.
DR InterPro; IPR000395; Bot/tetX_LC.
DR InterPro; IPR036248; Clostridium_toxin_transloc.
DR InterPro; IPR013320; ConA-like_dom_sf.
DR InterPro; IPR011065; Kunitz_inhibitor_STI-like_sf.
DR InterPro; IPR013104; Toxin_rcpt-bd_C.
DR InterPro; IPR012928; Toxin_rcpt-bd_N.
DR InterPro; IPR012500; Toxin_trans.
DR Pfam; PF01742; Peptidase_M27; 1.
DR Pfam; PF07951; Toxin_R_bind_C; 1.
DR Pfam; PF07953; Toxin_R_bind_N; 1.
DR Pfam; PF07952; Toxin_trans; 1.
DR PRINTS; PR00760; BONTOXILYSIN.
DR SUPFAM; SSF49899; SSF49899; 1.
DR SUPFAM; SSF50386; SSF50386; 1.
DR SUPFAM; SSF58091; SSF58091; 1.
DR PROSITE; PS00142; ZINC_PROTEASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond; Hydrolase;
KW Lipid-binding; Metal-binding; Metalloprotease; Neurotoxin; Pharmaceutical;
KW Protease; Secreted; Toxin; Virulence; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:2450068"
FT CHAIN 2..1291
FT /note="Botulinum neurotoxin type C"
FT /id="PRO_0000444905"
FT CHAIN 2..449
FT /note="Botulinum neurotoxin C light chain"
FT /id="PRO_0000029217"
FT CHAIN 450..1291
FT /note="Botulinum neurotoxin C heavy chain"
FT /id="PRO_0000029218"
FT REGION 450..865
FT /note="Translocation domain (TD)"
FT /evidence="ECO:0000250|UniProtKB:P0DPI0"
FT REGION 490..541
FT /note="Belt"
FT /evidence="ECO:0000250|UniProtKB:P10844"
FT REGION 866..1093
FT /note="N-terminus of receptor binding domain (N-RBD)"
FT /evidence="ECO:0000250|UniProtKB:P0DPI0"
FT REGION 1094..1291
FT /note="C-terminus of receptor binding domain (C-RBD)"
FT /evidence="ECO:0000250|UniProtKB:P0DPI0"
FT REGION 1269..1283
FT /note="Ganglioside-binding loop"
FT /evidence="ECO:0000305|PubMed:20731382,
FT ECO:0000305|PubMed:21542861"
FT MOTIF 1256..1258
FT /note="Host ganglioside-binding motif"
FT /evidence="ECO:0000250|UniProtKB:P10844,
FT ECO:0000305|PubMed:19650874"
FT ACT_SITE 230
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095"
FT BINDING 229
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:17718519, ECO:0007744|PDB:2QN0"
FT BINDING 233
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10095,
FT ECO:0000269|PubMed:17718519, ECO:0007744|PDB:2QN0"
FT BINDING 269
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:17718519,
FT ECO:0007744|PDB:2QN0"
FT BINDING 1119
FT /ligand="ganglioside GD1a (d18:1(4E))"
FT /ligand_id="ChEBI:CHEBI:78445"
FT /note="GBP2 binding site"
FT /evidence="ECO:0000305|PubMed:23027864"
FT BINDING 1126..1129
FT /ligand="ganglioside GD1b (d18:1(4E))"
FT /ligand_id="ChEBI:CHEBI:87785"
FT /note="Sia-1 binding site"
FT /evidence="ECO:0000305|PubMed:21542861,
FT ECO:0007744|PDB:3R4S"
FT BINDING 1146
FT /ligand="ganglioside GD1b (d18:1(4E))"
FT /ligand_id="ChEBI:CHEBI:87785"
FT /note="Sia-1 binding site"
FT /evidence="ECO:0000305|PubMed:21542861,
FT ECO:0007744|PDB:3R4S"
FT BINDING 1247..1250
FT /ligand="ganglioside GD1a (d18:1(4E))"
FT /ligand_id="ChEBI:CHEBI:78445"
FT /note="GBP2 binding site"
FT /evidence="ECO:0000305|PubMed:23027864"
FT BINDING 1281
FT /ligand="ganglioside GD1a (d18:1(4E))"
FT /ligand_id="ChEBI:CHEBI:78445"
FT /note="GBP2 binding site"
FT /evidence="ECO:0000305|PubMed:23027864"
FT DISULFID 437..453
FT /note="Interchain (between light and heavy chains)"
FT /evidence="ECO:0000250|UniProtKB:P10844, ECO:0000305"
FT MUTAGEN 1119
FT /note="Y->A: Receptor-binding domain (RBD) no longer binds
FT eukaryotic gangliosides GD1a or GM1a, reduced GT1b binding,
FT GD1b binding unaffected. RBD fragment enters neurons but
FT does not compartmentalize normally; uptake is not
FT stimulated by K(+)."
FT /evidence="ECO:0000269|PubMed:23027864"
FT MUTAGEN 1126
FT /note="A->K: Receptor-binding domain (RBD) no longer binds
FT eukaryotic gangliosides GM1a, GD1b, reduced binding of GD1a
FT and GT1b. RBD fragment does not enter neurons; uptake is
FT not stimulated by K(+)."
FT /evidence="ECO:0000269|PubMed:23027864"
FT MUTAGEN 1146
FT /note="Y->A: Whole toxin has dramatically reduced
FT toxicity."
FT /evidence="ECO:0000269|PubMed:21542861"
FT MUTAGEN 1179
FT /note="Y->S: Receptor-binding domain (RBD) has decreased
FT binding to neurons. Greatly decreased binding to neurons;
FT when associated with L-1258. Whole toxin has greatly
FT decreased toxicity, even less toxic; when associated with
FT L-1258. Decreased binding to mixed gangliosides, even less
FT binding to mixed gangliosides; when associated with L-
FT 1258."
FT /evidence="ECO:0000269|PubMed:21542861"
FT MUTAGEN 1193
FT /note="H->A: No effect on receptor-binding domain (RBD)
FT binding to eukaryotic gangliosides."
FT /evidence="ECO:0000269|PubMed:23027864"
FT MUTAGEN 1203
FT /note="L->F: Receptor-binding domain (RBD) has decreased
FT binding to neurons. Whole toxin has greatly decreased
FT toxicity. Decreased binding to mixed gangliosides."
FT /evidence="ECO:0000269|PubMed:21542861"
FT MUTAGEN 1258..1259
FT /note="WY->AA: Whole toxin has greatly decreased toxicity."
FT /evidence="ECO:0000269|PubMed:21542861"
FT MUTAGEN 1258
FT /note="W->A: Receptor-binding domain (RBD) has greatly
FT reduced binding of ganglioside GD1b, no longer binds
FT neurons."
FT /evidence="ECO:0000269|PubMed:20731382"
FT MUTAGEN 1258
FT /note="W->L: Receptor-binding domain (RBD) has decreased
FT binding to neurons (Ref.16). Greatly decreased binding to
FT neurons; when associated with S-1179. Whole toxin has
FT greatly decreased toxicity, even less toxic; when
FT associated with S-1179. Decreased binding to mixed
FT gangliosides, even less binding to mixed gangliosides; when
FT associated with S-1179."
FT /evidence="ECO:0000269|PubMed:19650874,
FT ECO:0000269|PubMed:21542861"
FT MUTAGEN 1281
FT /note="S->Y: Receptor-binding domain (RBD) has decreased
FT binding to neurons. Whole toxin has decreased toxicity and
FT decreased binding to mixed gangliosides."
FT /evidence="ECO:0000269|PubMed:21542861"
FT CONFLICT 85
FT /note="T -> P (in Ref. 1; CAA37780)"
FT STRAND 16..23
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 34..40
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 43..46
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 53..55
FT /evidence="ECO:0007829|PDB:2QN0"
FT TURN 74..77
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 80..97
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 101..112
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 126..128
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 134..141
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 143..152
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 155..159
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 169..171
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 181..183
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 184..186
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 190..193
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 201..207
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 223..238
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 248..253
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 256..258
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 260..266
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 267..273
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 275..280
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 283..304
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 309..312
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 313..318
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 319..330
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 344..356
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 360..366
FT /evidence="ECO:0007829|PDB:2QN0"
FT STRAND 372..374
FT /evidence="ECO:0007829|PDB:2QN0"
FT TURN 390..392
FT /evidence="ECO:0007829|PDB:2QN0"
FT TURN 395..397
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 402..404
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 411..413
FT /evidence="ECO:0007829|PDB:2QN0"
FT TURN 415..417
FT /evidence="ECO:0007829|PDB:2QN0"
FT HELIX 426..428
FT /evidence="ECO:0007829|PDB:3DEB"
FT HELIX 867..870
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 872..878
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 880..885
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 887..889
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 892..898
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 909..915
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 916..918
FT /evidence="ECO:0007829|PDB:3N7K"
FT STRAND 920..924
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 927..933
FT /evidence="ECO:0007829|PDB:3R4S"
FT TURN 934..936
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 937..947
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 956..963
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 966..973
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 976..984
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 987..994
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 997..999
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1008..1015
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1018..1024
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1027..1033
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1044..1052
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1067..1078
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 1082..1091
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1103..1105
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1107..1109
FT /evidence="ECO:0007829|PDB:3N7K"
FT STRAND 1111..1116
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 1117..1119
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1122..1127
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1130..1135
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1148..1155
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1159..1161
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1167..1174
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1177..1183
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1191..1193
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1198..1205
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 1212..1214
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1216..1222
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1227..1234
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1241..1252
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1261..1269
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 1273..1276
FT /evidence="ECO:0007829|PDB:3R4S"
FT HELIX 1280..1282
FT /evidence="ECO:0007829|PDB:3R4S"
FT STRAND 1284..1288
FT /evidence="ECO:0007829|PDB:3R4S"
SQ SEQUENCE 1291 AA; 148870 MW; 4A21DB35B8743CF8 CRC64;
MPITINNFNY SDPVDNKNIL YLDTHLNTLA NEPEKAFRIT GNIWVIPDRF SRNSNPNLNK
PPRVTSPKSG YYDPNYLSTD SDKDTFLKEI IKLFKRINSR EIGEELIYRL STDIPFPGNN
NTPINTFDFD VDFNSVDVKT RQGNNWVKTG SINPSVIITG PRENIIDPET STFKLTNNTF
AAQEGFGALS IISISPRFML TYSNATNDVG EGRFSKSEFC MDPILILMHE LNHAMHNLYG
IAIPNDQTIS SVTSNIFYSQ YNVKLEYAEI YAFGGPTIDL IPKSARKYFE EKALDYYRSI
AKRLNSITTA NPSSFNKYIG EYKQKLIRKY RFVVESSGEV TVNRNKFVEL YNELTQIFTE
FNYAKIYNVQ NRKIYLSNVY TPVTANILDD NVYDIQNGFN IPKSNLNVLF MGQNLSRNPA
LRKVNPENML YLFTKFCHKA IDGRSLYNKT LDCRELLVKN TDLPFIGDIS DVKTDIFLRK
DINEETEVIY YPDNVSVDQV ILSKNTSEHG QLDLLYPSID SESEILPGEN QVFYDNRTQN
VDYLNSYYYL ESQKLSDNVE DFTFTRSIEE ALDNSAKVYT YFPTLANKVN AGVQGGLFLM
WANDVVEDFT TNILRKDTLD KISDVSAIIP YIGPALNISN SVRRGNFTEA FAVTGVTILL
EAFPEFTIPA LGAFVIYSKV QERNEIIKTI DNCLEQRIKR WKDSYEWMMG TWLSRIITQF
NNISYQMYDS LNYQAGAIKA KIDLEYKKYS GSDKENIKSQ VENLKNSLDV KISEAMNNIN
KFIRECSVTY LFKNMLPKVI DELNEFDRNT KAKLINLIDS HNIILVGEVD KLKAKVNNSF
QNTIPFNIFS YTNNSLLKDI INEYFNNIND SKILSLQNRK NTLVDTSGYN AEVSEEGDVQ
LNPIFPFDFK LGSSGEDRGK VIVTQNENIV YNSMYESFSI SFWIRINKWV SNLPGYTIID
SVKNNSGWSI GIISNFLVFT LKQNEDSEQS INFSYDISNN APGYNKWFFV TVTNNMMGNM
KIYINGKLID TIKVKELTGI NFSKTITFEI NKIPDTGLIT SDSDNINMWI RDFYIFAKEL
DGKDINILFN SLQYTNVVKD YWGNDLRYNK EYYMVNIDYL NRYMYANSRQ IVFNTRRNNN
DFNEGYKIII KRIRGNTNDT RVRGGDILYF DMTINNKAYN LFMKNETMYA DNHSTEDIYA
IGLREQTKDI NDNIIFQIQP MNNTYYYASQ IFKSNFNGEN ISGICSIGTY RFRLGGDWYR
HNYLVPTVKQ GNYASLLEST STHWGFVPVS E
