3SA3_NAJAT
ID 3SA3_NAJAT Reviewed; 81 AA.
AC P60301; P01444; Q9PS23; Q9W6W7;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 02-FEB-2004, sequence version 1.
DT 25-MAY-2022, entry version 90.
DE RecName: Full=Cytotoxin 3;
DE AltName: Full=Cardiotoxin 3 {ECO:0000303|PubMed:10708798};
DE Short=CTX-3;
DE Short=CTX3;
DE AltName: Full=Cardiotoxin A3 {ECO:0000303|PubMed:16407244, ECO:0000303|PubMed:8182052};
DE Short=CTX A3 {ECO:0000303|PubMed:16407244, ECO:0000303|PubMed:8182052};
DE AltName: Full=Cardiotoxin III {ECO:0000303|PubMed:8619792};
DE AltName: Full=Cardiotoxin analog III;
DE Short=CTX III;
DE Flags: Precursor;
OS Naja atra (Chinese cobra).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Elapidae; Elapinae; Naja.
OX NCBI_TaxID=8656;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RX PubMed=8619792; DOI=10.1006/bbrc.1996.0191;
RA Chang L.-S., Wu P.-F., Lin J.;
RT "cDNA sequence analysis and expression of cardiotoxins from Taiwan Cobra.";
RL Biochem. Biophys. Res. Commun. 219:116-121(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RA Chu R.C., Yang C.-C.;
RL Submitted (DEC-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RA Qian Y.C., Fan C.Y., Gong Y., Yang S.-L.;
RT "cDNA cloning and expression of cardiotoxins from Chinese continental
RT cobra.";
RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=10708798; DOI=10.1016/s0041-0101(99)00218-4;
RA Chang L.-S., Huang H.-B., Lin S.-R.;
RT "The multiplicity of cardiotoxins from Naja naja atra (Taiwan cobra)
RT venom.";
RL Toxicon 38:1065-1076(2000).
RN [5]
RP PROTEIN SEQUENCE OF 22-81, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=5518165; DOI=10.1016/0006-291x(70)90509-7;
RA Narita K., Lee C.Y.;
RT "The amino acid sequence of cardiotoxin from Formosan cobra (Naja naja
RT atra) venom.";
RL Biochem. Biophys. Res. Commun. 41:339-343(1970).
RN [6]
RP PROTEIN SEQUENCE OF 22-81, AND SEQUENCE REVISION.
RC TISSUE=Venom;
RX PubMed=955081; DOI=10.1016/0014-5793(76)80506-6;
RA Hayashi K., Takechi M., Kaneda N., Sasaki T.;
RT "Amino acid sequence of cardiotoxin from the venom of Naja naja atra.";
RL FEBS Lett. 66:210-214(1976).
RN [7]
RP PROTEIN SEQUENCE OF 22-81, AND FUNCTION AS AN INHIBITOR OF PKC.
RX PubMed=8448165; DOI=10.1021/bi00059a025;
RA Chiou S.-H., Raynor R.L., Zheng B., Chambers T.C., Kuo J.F.;
RT "Cobra venom cardiotoxin (cytotoxin) isoforms and neurotoxin: comparative
RT potency of protein kinase C inhibition and cancer cell cytotoxicity and
RT modes of enzyme inhibition.";
RL Biochemistry 32:2062-2067(1993).
RN [8]
RP FUNCTION, AND APPARTENANCE TO P-TYPE CYTOTOXIN GROUP.
RX PubMed=8182052; DOI=10.1016/s0021-9258(17)36647-4;
RA Chien K.-Y., Chiang C.-M., Hseu Y.-C., Vyas A.A., Rule G.S., Wu W.-G.;
RT "Two distinct types of cardiotoxin as revealed by the structure and
RT activity relationship of their interaction with zwitterionic phospholipid
RT dispersions.";
RL J. Biol. Chem. 269:14473-14483(1994).
RN [9]
RP FUNCTION ON MEMBRANES.
RX PubMed=9245415; DOI=10.1021/bi970413l;
RA Sue S.-C., Rajan P.K., Chen T.-S., Hsieh C.-H., Wu W.-G.;
RT "Action of Taiwan cobra cardiotoxin on membranes: binding modes of a beta-
RT sheet polypeptide with phosphatidylcholine bilayers.";
RL Biochemistry 36:9826-9836(1997).
RN [10]
RP INTERACTION WITH KCNIP1.
RX PubMed=15184042; DOI=10.1016/j.bbrc.2004.05.064;
RA Lin Y.-L., Lin S.-R., Wu T.T., Chang L.-S.;
RT "Evidence showing an intermolecular interaction between KChIP proteins and
RT Taiwan cobra cardiotoxins.";
RL Biochem. Biophys. Res. Commun. 319:720-724(2004).
RN [11]
RP FUNCTION ON MITOCHONDRIA.
RX PubMed=15922335; DOI=10.1016/j.febslet.2005.05.006;
RA Wang C.-H., Wu W.-G.;
RT "Amphiphilic beta-sheet cobra cardiotoxin targets mitochondria and disrupts
RT its network.";
RL FEBS Lett. 579:3169-3174(2005).
RN [12]
RP FUNCTION, INTERACTION WITH GLYCOSPHINGOLIPID, AND SUBUNIT.
RX PubMed=16263708; DOI=10.1074/jbc.m507880200;
RA Wang C.-H., Liu J.H., Lee S.C., Hsiao C.D., Wu W.-G.;
RT "Glycosphingolipid-facilitated membrane insertion and internalization of
RT cobra cardiotoxin. The sulfatide-cardiotoxin complex structure in a
RT membrane-like environment suggests a lipid-dependent cell-penetrating
RT mechanism for membrane binding polypeptides.";
RL J. Biol. Chem. 281:656-667(2006).
RN [13]
RP FUNCTION, AND BINDING TO INTEGRIN ALPHA-V/BETA-3.
RX PubMed=16407244; DOI=10.1074/jbc.m513035200;
RA Wu P.-L., Lee S.-C., Chuang C.-C., Mori S., Akakura N., Wu W.-G.,
RA Takada Y.;
RT "Non-cytotoxic cobra cardiotoxin A5 binds to alpha(v)beta3 integrin and
RT inhibits bone resorption. Identification of cardiotoxins as non-RGD
RT integrin-binding proteins of the Ly-6 family.";
RL J. Biol. Chem. 281:7937-7945(2006).
RN [14]
RP FUNCTION, AND BINDING TO HEPARIN.
RX PubMed=17685633; DOI=10.1021/bi700995v;
RA Tjong S.C., Chen T.S., Huang W.N., Wu W.G.;
RT "Structures of heparin-derived tetrasaccharide bound to cobra cardiotoxins:
RT heparin binding at a single protein site with diverse side chain
RT interactions.";
RL Biochemistry 46:9941-9952(2007).
RN [15]
RP FUNCTION.
RX PubMed=17714752; DOI=10.1016/j.toxicon.2007.06.011;
RA Chen K.-C., Kao P.-H., Lin S.-R., Chang L.-S.;
RT "The mechanism of cytotoxicity by Naja naja atra cardiotoxin 3 is
RT physically distant from its membrane-damaging effect.";
RL Toxicon 50:816-824(2007).
RN [16]
RP STRUCTURE BY NMR, AND DISULFIDE BONDS.
RX PubMed=8308891; DOI=10.1006/jmbi.1994.1082;
RA Bhaskaran R., Huang C.C., Chang D.K., Yu C.;
RT "Cardiotoxin III from the Taiwan cobra (Naja naja atra). Determination of
RT structure in solution and comparison with short neurotoxins.";
RL J. Mol. Biol. 235:1291-1301(1994).
RN [17]
RP STRUCTURE BY NMR, AND DISULFIDE BONDS.
RX PubMed=11669614; DOI=10.1021/bi010848f;
RA Sue S.-C., Jarrell H.C., Brisson J.-R., Wu W.-G.;
RT "Dynamic characterization of the water binding loop in the P-type
RT cardiotoxin: implication for the role of the bound water molecule.";
RL Biochemistry 40:12782-12794(2001).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 22-81 WITH ANIONIC LIPID SDS,
RP DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=12660250; DOI=10.1074/jbc.m208650200;
RA Forouhar F., Huang W.-N., Liu J.-H., Chien K.-Y., Wu W.-G., Hsiao C.-D.;
RT "Structural basis of membrane-induced cardiotoxin A3 oligomerization.";
RL J. Biol. Chem. 278:21980-21988(2003).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 22-81, AND DISULFIDE BONDS.
RX PubMed=15590643; DOI=10.1074/jbc.m412398200;
RA Lee S.-C., Guan H.-H., Wang C.-H., Huang W.-N., Tjong S.-C., Chen C.-J.,
RA Wu W.-G.;
RT "Structural basis of citrate-dependent and heparan sulfate-mediated cell
RT surface retention of cobra cardiotoxin A3.";
RL J. Biol. Chem. 280:9567-9577(2005).
CC -!- FUNCTION: Basic protein that binds to cell membrane and depolarizes
CC cardiomyocytes. This cytotoxin also possesses lytic activity on many
CC other cells, including red blood cells (PubMed:8182052). Interaction
CC with sulfatides in the cell membrane induces pore formation and cell
CC internalization. Cytotoxicity is due to pore formation, and to another
CC mechanism independent of membrane-damaging activity. When internalized,
CC it targets the mitochondrial membrane and induces mitochondrial
CC swelling and fragmentation. It inhibits protein kinases C. It binds to
CC the integrin alpha-V/beta-3 (ITGAV/ITGB3) with a moderate affinity
CC (PubMed:16407244). It also binds with high affinity to heparin
CC (PubMed:17685633). {ECO:0000269|PubMed:15922335,
CC ECO:0000269|PubMed:16263708, ECO:0000269|PubMed:16407244,
CC ECO:0000269|PubMed:17714752, ECO:0000269|PubMed:8182052,
CC ECO:0000269|PubMed:8448165, ECO:0000269|PubMed:9245415}.
CC -!- SUBUNIT: Monomer in solution; Homodimer and oligomer in the presence of
CC negatively charged lipids forming a pore with a size ranging between 20
CC and 30 Angstroms (PubMed:16263708,PubMed:12660250). Interacts with Kv
CC channel-interacting protein 1 (KCNIP1) in a calcium-independent manner
CC (PubMed:15184042). {ECO:0000269|PubMed:12660250,
CC ECO:0000269|PubMed:15184042, ECO:0000269|PubMed:16263708}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:5518165}. Target
CC cell membrane {ECO:0000305|PubMed:12660250,
CC ECO:0000305|PubMed:16263708}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- MISCELLANEOUS: Is classified as a P-type cytotoxin, since a proline
CC residue stands at position 51 (Pro-31 in standard classification).
CC {ECO:0000305|PubMed:8182052}.
CC -!- SIMILARITY: Belongs to the snake three-finger toxin family. Short-chain
CC subfamily. Type IA cytotoxin sub-subfamily. {ECO:0000305}.
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DR EMBL; Z54227; CAA90963.1; -; mRNA.
DR EMBL; U58486; AAB18382.1; -; mRNA.
DR EMBL; U42585; AAB01541.1; -; mRNA.
DR EMBL; AJ007796; CAA07686.1; -; mRNA.
DR EMBL; AJ238735; CAB42055.1; -; Genomic_DNA.
DR PIR; JC4620; H3NJ3F.
DR PDB; 1H0J; X-ray; 1.90 A; A/B/C=22-81.
DR PDB; 1I02; NMR; -; A=22-81.
DR PDB; 1XT3; X-ray; 2.40 A; A/B=22-81.
DR PDB; 2BHI; X-ray; 2.31 A; A/B=22-81.
DR PDB; 2CRS; NMR; -; A=22-81.
DR PDB; 2CRT; NMR; -; A=22-81.
DR PDBsum; 1H0J; -.
DR PDBsum; 1I02; -.
DR PDBsum; 1XT3; -.
DR PDBsum; 2BHI; -.
DR PDBsum; 2CRS; -.
DR PDBsum; 2CRT; -.
DR AlphaFoldDB; P60301; -.
DR BMRB; P60301; -.
DR SMR; P60301; -.
DR EvolutionaryTrace; P60301; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0044179; P:hemolysis in another organism; IEA:UniProtKB-KW.
DR CDD; cd00206; snake_toxin; 1.
DR Gene3D; 2.10.60.10; -; 1.
DR InterPro; IPR003572; Cytotoxin_Cobra.
DR InterPro; IPR003571; Snake_3FTx.
DR InterPro; IPR045860; Snake_toxin-like_sf.
DR InterPro; IPR018354; Snake_toxin_con_site.
DR PRINTS; PR00282; CYTOTOXIN.
DR SUPFAM; SSF57302; SSF57302; 1.
DR PROSITE; PS00272; SNAKE_TOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cardiotoxin; Cytolysis; Direct protein sequencing;
KW Disulfide bond; Hemolysis; Membrane; Secreted; Signal;
KW Target cell membrane; Target membrane; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:5518165,
FT ECO:0000269|PubMed:8448165, ECO:0000269|PubMed:955081"
FT CHAIN 22..81
FT /note="Cytotoxin 3"
FT /evidence="ECO:0000269|PubMed:5518165,
FT ECO:0000269|PubMed:8448165, ECO:0000269|PubMed:955081"
FT /id="PRO_0000035370"
FT DISULFID 24..42
FT /evidence="ECO:0000269|PubMed:11669614,
FT ECO:0000269|PubMed:12660250, ECO:0000269|PubMed:15590643,
FT ECO:0000269|PubMed:8308891, ECO:0000312|PDB:1H0J,
FT ECO:0000312|PDB:1I02, ECO:0000312|PDB:1XT3,
FT ECO:0000312|PDB:2BHI, ECO:0000312|PDB:2CRS,
FT ECO:0000312|PDB:2CRT"
FT DISULFID 35..59
FT /evidence="ECO:0000269|PubMed:11669614,
FT ECO:0000269|PubMed:12660250, ECO:0000269|PubMed:15590643,
FT ECO:0000269|PubMed:8308891, ECO:0000312|PDB:1H0J,
FT ECO:0000312|PDB:1I02, ECO:0000312|PDB:1XT3,
FT ECO:0000312|PDB:2BHI, ECO:0000312|PDB:2CRS,
FT ECO:0000312|PDB:2CRT"
FT DISULFID 63..74
FT /evidence="ECO:0000269|PubMed:11669614,
FT ECO:0000269|PubMed:12660250, ECO:0000269|PubMed:15590643,
FT ECO:0000269|PubMed:8308891, ECO:0000312|PDB:1H0J,
FT ECO:0000312|PDB:1I02, ECO:0000312|PDB:1XT3,
FT ECO:0000312|PDB:2BHI, ECO:0000312|PDB:2CRS,
FT ECO:0000312|PDB:2CRT"
FT DISULFID 75..80
FT /evidence="ECO:0000269|PubMed:11669614,
FT ECO:0000269|PubMed:12660250, ECO:0000269|PubMed:15590643,
FT ECO:0000269|PubMed:8308891, ECO:0000312|PDB:1H0J,
FT ECO:0000312|PDB:1I02, ECO:0000312|PDB:1XT3,
FT ECO:0000312|PDB:2BHI, ECO:0000312|PDB:2CRS,
FT ECO:0000312|PDB:2CRT"
FT CONFLICT 9..11
FT /note="VVV -> EEE (in Ref. 4; CAB42055)"
FT /evidence="ECO:0000305"
FT CONFLICT 59
FT /note="C -> R (in Ref. 1; CAA90963)"
FT /evidence="ECO:0000305"
FT STRAND 23..25
FT /evidence="ECO:0007829|PDB:1H0J"
FT STRAND 32..34
FT /evidence="ECO:0007829|PDB:1H0J"
FT STRAND 36..38
FT /evidence="ECO:0007829|PDB:2CRS"
FT STRAND 41..47
FT /evidence="ECO:0007829|PDB:1H0J"
FT STRAND 49..51
FT /evidence="ECO:0007829|PDB:2CRS"
FT STRAND 56..62
FT /evidence="ECO:0007829|PDB:1H0J"
FT STRAND 68..75
FT /evidence="ECO:0007829|PDB:1H0J"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:2CRS"
SQ SEQUENCE 81 AA; 9038 MW; 70FE0A82FAC9DC95 CRC64;
MKTLLLTLVV VTIVCLDLGY TLKCNKLVPL FYKTCPAGKN LCYKMFMVAT PKVPVKRGCI
DVCPKSSLLV KYVCCNTDRC N
