3SA4_NAJAT
ID 3SA4_NAJAT Reviewed; 81 AA.
AC P01443;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1998, sequence version 2.
DT 25-MAY-2022, entry version 121.
DE RecName: Full=Cytotoxin 4;
DE Short=CTX-4M;
DE Short=CTX4;
DE AltName: Full=Cardiotoxin A4 {ECO:0000303|PubMed:16407244, ECO:0000303|PubMed:8182052};
DE Short=CTX A4 {ECO:0000303|PubMed:16407244, ECO:0000303|PubMed:8182052};
DE AltName: Full=Cardiotoxin analog IV {ECO:0000303|PubMed:849468};
DE Short=CTX IV {ECO:0000303|PubMed:849468};
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 [GENOMIC DNA / MRNA].
RC TISSUE=Liver, and Venom gland;
RX PubMed=9367842; DOI=10.1006/bbrc.1997.7549;
RA Chang L.-S., Lin J., Chou Y.-C., Hong E.;
RT "Genomic structures of cardiotoxin 4 and cobrotoxin from Naja naja atra
RT (Taiwan cobra).";
RL Biochem. Biophys. Res. Commun. 239:756-762(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom gland;
RA Chu R.C., Yang C.-C.;
RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP PROTEIN SEQUENCE OF 22-81, SUBCELLULAR LOCATION, AND TOXIC DOSE.
RC TISSUE=Venom;
RX PubMed=992063; DOI=10.1016/0014-5793(76)80761-2;
RA Kaneda N., Sasaki T., Hayashi K.;
RT "The amino acid sequence of cardiotoxin-analogue IV from the venom of Naja
RT naja atra.";
RL FEBS Lett. 70:217-222(1976).
RN [4]
RP PROTEIN SEQUENCE OF 22-81, AND TOXIC DOSE.
RC TISSUE=Venom;
RX PubMed=849468; DOI=10.1016/0005-2795(77)90040-x;
RA Kaneda N., Sasaki T., Hayashi K.;
RT "Primary structures of cardiotoxin analogues II and IV from the venom of
RT Naja naja atra.";
RL Biochim. Biophys. Acta 491:53-66(1977).
RN [5]
RP PROTEIN SEQUENCE OF 22-81, AND FUNCTION AS AN INHIBITOR OF PKC.
RC TISSUE=Venom;
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 [6]
RP FUNCTION, AND APPARTENANCE TO S-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 [7]
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 [8]
RP STRUCTURE BY NMR, FUNCTION, AND DISULFIDE BONDS.
RX PubMed=9398182; DOI=10.1021/bi971107a;
RA Jang J.-Y., Kumar T.K.S., Jayaraman G., Yang P.-W., Yu C.;
RT "Comparison of the hemolytic activity and solution structures of two snake
RT venom cardiotoxin analogues which only differ in their N-terminal amino
RT acid.";
RL Biochemistry 36:14635-14641(1997).
CC -!- FUNCTION: Basic protein that bind to cell membrane and depolarizes
CC cardiomyocytes. This cytotoxin also shows lytic activities, but 2-fold
CC more important than that of CTX-A2. It binds to the integrin alpha-
CC V/beta-3 with a moderate affinity. Inhibits protein kinase C. It may
CC interact with sulfatides in the cell membrane, which induces pore
CC formation and cell internalization and is responsible for cytotoxicity
CC in cardiomyocytes. It also may target the mitochondrial membrane and
CC induces mitochondrial swelling and fragmentation.
CC {ECO:0000269|PubMed:16407244, ECO:0000269|PubMed:8448165,
CC ECO:0000269|PubMed:9398182}.
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. {ECO:0000250|UniProtKB:P60301}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:992063}. Target cell
CC membrane {ECO:0000250|UniProtKB:P60301}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland. {ECO:0000305}.
CC -!- TOXIC DOSE: LD(50) is 2.1 mg/kg by intravenous injection into mice.
CC {ECO:0000269|PubMed:992063}.
CC -!- TOXIC DOSE: LD(50) is 48 mg/kg by subcutaneous injection into mice.
CC {ECO:0000269|PubMed:992063}.
CC -!- MISCELLANEOUS: Is classified as a S-type cytotoxin, since a serine
CC residue stands at position 49 (Ser-29 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; Y12491; CAA73096.1; -; mRNA.
DR EMBL; Y12493; CAA73098.1; -; Genomic_DNA.
DR EMBL; AF031473; AAB86637.1; -; mRNA.
DR PIR; JC5768; H3NJ4F.
DR PDB; 1KBS; NMR; -; A=22-81.
DR PDB; 1KBT; NMR; -; A=22-81.
DR PDB; 4OM5; X-ray; 2.55 A; A/B/C/D=22-81.
DR PDBsum; 1KBS; -.
DR PDBsum; 1KBT; -.
DR PDBsum; 4OM5; -.
DR AlphaFoldDB; P01443; -.
DR SMR; P01443; -.
DR EvolutionaryTrace; P01443; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-KW.
DR GO; GO:0004860; F:protein kinase inhibitor activity; 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; Protein kinase inhibitor; Secreted;
KW Signal; Target cell membrane; Target membrane; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000269|PubMed:8448165,
FT ECO:0000269|PubMed:849468, ECO:0000269|PubMed:992063"
FT CHAIN 22..81
FT /note="Cytotoxin 4"
FT /evidence="ECO:0000269|PubMed:8448165,
FT ECO:0000269|PubMed:849468, ECO:0000269|PubMed:992063"
FT /id="PRO_0000035375"
FT DISULFID 24..42
FT /evidence="ECO:0000269|PubMed:9398182,
FT ECO:0000312|PDB:1KBS, ECO:0000312|PDB:1KBT,
FT ECO:0000312|PDB:4OM5"
FT DISULFID 35..59
FT /evidence="ECO:0000269|PubMed:9398182,
FT ECO:0000312|PDB:1KBS, ECO:0000312|PDB:1KBT,
FT ECO:0000312|PDB:4OM5"
FT DISULFID 63..74
FT /evidence="ECO:0000269|PubMed:9398182,
FT ECO:0000312|PDB:1KBS, ECO:0000312|PDB:1KBT,
FT ECO:0000312|PDB:4OM5"
FT DISULFID 75..80
FT /evidence="ECO:0000269|PubMed:9398182,
FT ECO:0000312|PDB:1KBS, ECO:0000312|PDB:1KBT,
FT ECO:0000312|PDB:4OM5"
FT STRAND 23..25
FT /evidence="ECO:0007829|PDB:4OM5"
FT STRAND 27..30
FT /evidence="ECO:0007829|PDB:1KBS"
FT STRAND 32..34
FT /evidence="ECO:0007829|PDB:4OM5"
FT STRAND 41..47
FT /evidence="ECO:0007829|PDB:4OM5"
FT STRAND 55..62
FT /evidence="ECO:0007829|PDB:4OM5"
FT STRAND 69..75
FT /evidence="ECO:0007829|PDB:4OM5"
FT TURN 78..80
FT /evidence="ECO:0007829|PDB:1KBS"
SQ SEQUENCE 81 AA; 9084 MW; 182274FCE4D957A4 CRC64;
MKTLLLTLVV VTIVCLDLGY TRKCNKLVPL FYKTCPAGKN LCYKMFMVSN LTVPVKRGCI
DVCPKNSALV KYVCCNTDRC N
