MYC2_CRODU
ID MYC2_CRODU Reviewed; 65 AA.
AC Q9PWF3; P01475;
DT 27-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 25-MAY-2022, entry version 77.
DE RecName: Full=Crotamine {ECO:0000303|PubMed:1176086};
DE Short=Crt;
DE AltName: Full=Myotoxin;
DE Flags: Precursor;
GN Name=CRO2; Synonyms=CRT-P1;
OS Crotalus durissus terrificus (South American rattlesnake).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera;
OC Serpentes; Colubroidea; Viperidae; Crotalinae; Crotalus.
OX NCBI_TaxID=8732;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Martinopolis; TISSUE=Venom gland;
RX PubMed=10484745; DOI=10.1016/s0041-0101(98)00226-8;
RA Radis-Baptista G., Oguiura N., Hayashi M.A.F., Camargo M.E., Grego K.F.,
RA Oliveira E.B., Yamane T.;
RT "Nucleotide sequence of crotamine isoform precursors from a single South
RT American rattlesnake (Crotalus durissus terrificus).";
RL Toxicon 37:973-984(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=14757205; DOI=10.1016/j.toxicon.2003.10.019;
RA Radis-Baptista G., Kubo T., Oguiura N., Svartman M., Almeida T.M.B.,
RA Batistic R.F., Oliveira E.B., Vianna-Morgante A.M., Yamane T.;
RT "Structure and chromosomal localization of the gene for crotamine, a toxin
RT from the South American rattlesnake, Crotalus durissus terrificus.";
RL Toxicon 42:747-752(2003).
RN [3]
RP PROTEIN SEQUENCE OF 23-64, FUNCTION, TOXIC DOSE, AND SUBCELLULAR LOCATION.
RX PubMed=1176086;
RA Laure C.J.;
RT "The primary structure of crotamine.";
RL Hoppe-Seyler's Z. Physiol. Chem. 356:213-215(1975).
RN [4]
RP PROTEIN SEQUENCE OF 23-42, MASS SPECTROMETRY, FUNCTION AS POTASSIUM CHANNEL
RP INHIBITOR, AND PROBABLE SITES AT TYR-23; LYS-24; ARG-55 AND TRP-56.
RX PubMed=22498659; DOI=10.1124/mol.112.078188;
RA Peigneur S., Orts D.J., Prieto da Silva A.R., Oguiura N., Boni-Mitake M.,
RA de Oliveira E.B., Zaharenko A.J., de Freitas J.C., Tytgat J.;
RT "Crotamine pharmacology revisited: novel insights based on the inhibition
RT of KV channels.";
RL Mol. Pharmacol. 82:90-96(2012).
RN [5]
RP FUNCTION.
RC TISSUE=Venom;
RX PubMed=667499; DOI=10.1111/j.1476-5381.1978.tb07811.x;
RA Chang C.C., Tseng K.H.;
RT "Effect of crotamine, a toxin of South American rattlesnake venom, on the
RT sodium channel of murine skeletal muscle.";
RL Br. J. Pharmacol. 63:551-559(1978).
RN [6]
RP FUNCTION, AND TOXIC DOSE.
RX PubMed=9839677; DOI=10.1016/s0041-0101(98)00117-2;
RA Mancin A.C., Soares A.M., Andriao-Escarso S.H., Faca V.M., Greene L.J.,
RA Zuccolotto S., Pela I.R., Giglio J.R.;
RT "The analgesic activity of crotamine, a neurotoxin from Crotalus durissus
RT terrificus (South American rattlesnake) venom: a biochemical and
RT pharmacological study.";
RL Toxicon 36:1927-1937(1998).
RN [7]
RP FUNCTION AS CELL PENETRATING PEPTIDE.
RX PubMed=15231729; DOI=10.1096/fj.03-1459fje;
RA Kerkis A., Kerkis I., Radis-Baptista G., Oliveira E.B.,
RA Vianna-Morgante A.M., Pereira L.V., Yamane T.;
RT "Crotamine is a novel cell-penetrating protein from the venom of
RT rattlesnake Crotalus durissus terrificus.";
RL FASEB J. 18:1407-1409(2004).
RN [8]
RP FUNCTION AS CELL PENETRATING PEPTIDE.
RX PubMed=17491023; DOI=10.1074/jbc.m604876200;
RA Nascimento F.D., Hayashi M.A.F., Kerkis A., Oliveira V., Oliveira E.B.,
RA Radis-Baptista G., Nader H.B., Yamane T., Tersariol I.L., Kerkis I.;
RT "Crotamine mediates gene delivery into cells through the binding to heparan
RT sulfate proteoglycans.";
RL J. Biol. Chem. 282:21349-21360(2007).
RN [9]
RP FUNCTION.
RX PubMed=17588630; DOI=10.1016/j.toxicon.2007.04.026;
RA Rizzi C.T., Carvalho-de-Souza J.L., Schiavon E., Cassola A.C., Wanke E.,
RA Troncone L.R.;
RT "Crotamine inhibits preferentially fast-twitching muscles but is inactive
RT on sodium channels.";
RL Toxicon 50:553-562(2007).
RN [10]
RP FUNCTION.
RX PubMed=18662711; DOI=10.1016/j.toxicon.2008.06.029;
RA Hayashi M.A.F., Nascimento F.D., Kerkis A., Oliveira V., Oliveira E.B.,
RA Pereira A., Radis-Baptista G., Nader H.B., Yamane T., Kerkis I.,
RA Tersariol I.L.;
RT "Cytotoxic effects of crotamine are mediated through lysosomal membrane
RT permeabilization.";
RL Toxicon 52:508-517(2008).
RN [11]
RP FUNCTION AS ANTIMICROBIAL PEPTIDE, AND DOCKING STUDIES WITH POTASSIUM
RP CHANNELS.
RX PubMed=19706485; DOI=10.1073/pnas.0904465106;
RA Yount N.Y., Kupferwasser D., Spisni A., Dutz S.M., Ramjan Z.H., Sharma S.,
RA Waring A.J., Yeaman M.R.;
RT "Selective reciprocity in antimicrobial activity versus cytotoxicity of
RT hBD-2 and crotamine.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:14972-14977(2009).
RN [12]
RP BIOASSAY IN MOUSE MODELS OF MELANOMA.
RX PubMed=21834748; DOI=10.1517/13543784.2011.602064;
RA Pereira A., Kerkis A., Hayashi M.A.F., Pereira A.S., Silva F.S.,
RA Oliveira E.B., Prieto da Silva A.R., Yamane T., Radis-Baptista G.,
RA Kerkis I.;
RT "Crotamine toxicity and efficacy in mouse models of melanoma.";
RL Expert Opin. Invest. Drugs 20:1189-1200(2011).
RN [13]
RP FUNCTION AS ANTIBACTERIAL PEPTIDE.
RX PubMed=21386851; DOI=10.1038/ja.2011.10;
RA Oguiura N., Boni-Mitake M., Affonso R., Zhang G.;
RT "In vitro antibacterial and hemolytic activities of crotamine, a small
RT basic myotoxin from rattlesnake Crotalus durissus.";
RL J. Antibiot. 64:327-331(2011).
RN [14]
RP FUNCTION.
RX PubMed=22142367; DOI=10.1021/mp2000605;
RA Nascimento F.D., Sancey L., Pereira A., Rome C., Oliveira V.,
RA Oliveira E.B., Nader H.B., Yamane T., Kerkis I., Tersariol I.L., Coll J.L.,
RA Hayashi M.A.F.;
RT "The natural cell-penetrating peptide crotamine targets tumor tissue in
RT vivo and triggers a lethal calcium-dependent pathway in cultured cells.";
RL Mol. Pharm. 9:211-221(2012).
RN [15]
RP FUNCTION AS ANTIMICROBIAL PEPTIDE, SYNTHESIS OF 23-65, AND CIRCULAR
RP DICHROISM ANALYSIS.
RC TISSUE=Venom;
RX PubMed=23022146; DOI=10.1016/j.biochi.2012.09.019;
RA Yamane E.S., Bizerra F.C., Oliveira E.B., Moreira J.T., Rajabi M.,
RA Nunes G.L., de Souza A.O., da Silva I.D., Yamane T., Karpel R.L.,
RA Silva P.I. Jr., Hayashi M.A.F.;
RT "Unraveling the antifungal activity of a South American rattlesnake toxin
RT crotamine.";
RL Biochimie 95:231-240(2013).
RN [16]
RP REVIEW.
RX PubMed=21062230; DOI=10.1517/13543784.2010.534457;
RA Kerkis I., Silva F.S., Pereira A., Kerkis A., Radis-Baptista G.;
RT "Biological versatility of crotamine--a cationic peptide from the venom of
RT a South American rattlesnake.";
RL Expert Opin. Invest. Drugs 19:1515-1525(2010).
RN [17]
RP STRUCTURE BY NMR OF 23-64, AND DISULFIDE BONDS.
RX PubMed=12709056; DOI=10.1046/j.1432-1033.2003.03563.x;
RA Nicastro G., Franzoni L., de Chiara C., Mancin A.C., Giglio J.R.,
RA Spisni A.;
RT "Solution structure of crotamine, a Na+ channel affecting toxin from
RT Crotalus durissus terrificus venom.";
RL Eur. J. Biochem. 270:1969-1979(2003).
RN [18]
RP STRUCTURE BY NMR OF 23-64, AND DISULFIDE BONDS.
RX PubMed=16185738; DOI=10.1016/j.toxicon.2005.07.018;
RA Fadel V., Bettendorff P., Herrmann T., de Azevedo W.F. Jr., Oliveira E.B.,
RA Yamane T., Wuthrich K.;
RT "Automated NMR structure determination and disulfide bond identification of
RT the myotoxin crotamine from Crotalus durissus terrificus.";
RL Toxicon 46:759-767(2005).
CC -!- FUNCTION: Cationic peptide that possesses multiple functions. It acts
CC as a cell-penetrating peptide (CPP), and as a potent voltage-gated
CC potassium channel inhibitor. It exhibits antimicrobial activities, hind
CC limb paralysis, and severe muscle necrosis by a non-enzymatic
CC mechanism. As a cell-penetrating peptide, crotamine has high
CC specificity for actively proliferating cells, and interacts inside the
CC cell with subcellular and subnuclear structures, like vesicular
CC compartments, chromosomes and centrioles. It penetrates into the cells
CC as fast as five minutes after its addition to cell culture medium
CC (PubMed:18662711). In vivo, after intraperitoneal administration, it is
CC found in cells of peritoneal fluid and bone marrow, demonstrating
CC preferential nuclear and perinuclear localization. To enter the cell,
CC it interacts with the chains of heparan sulfate membrane proteoglycan
CC (HSPG), and is endocytosed (in complex with HSPG) in vesicles which are
CC transported into the cell with the help of clathrin. Inside the cell,
CC crotamine accumulates in lysosomal vesicles. As soon as the peptide
CC accumulates in endosomes/lysosomes vesicles, these compartments are
CC disrupted and their contents released into the cytosol. This loss of
CC lysosomal content induces cell death at high concentrations, or
CC promotes the distribution of crotamine in cytoplasmic compartments,
CC which is a step before crotamine nuclear uptake (PubMed:15231729,
CC PubMed:17491023). As a potassium channel inhibitor, this toxin
CC selectively inhibits Kv1.1/KCNA1, Kv1.2/KCNA2 and Kv1.3/KCNA3 channels
CC with an IC(50) of 369, 386 and 287 nM, respectively (PubMed:22498659).
CC The inhibition of Kv1.3/KCNA channels induced by this toxin occurs
CC rapidly and is voltage-independent. The channel inhibition is
CC reversible after washing, suggesting a pure and classical channel
CC blockage effect, without effects in potassium channel kinetics
CC (PubMed:22498659). As an antimicrobial peptide, crotamine shows
CC antibacterial activity against E.coli and B.subtilis, and antifungal
CC activity against Candida spp., Trichosporon spp. and C.neoformans. It
CC kills bacteria through membrane permeabilization.
CC {ECO:0000269|PubMed:1176086, ECO:0000269|PubMed:15231729,
CC ECO:0000269|PubMed:17491023, ECO:0000269|PubMed:17588630,
CC ECO:0000269|PubMed:18662711, ECO:0000269|PubMed:19706485,
CC ECO:0000269|PubMed:21386851, ECO:0000269|PubMed:22142367,
CC ECO:0000269|PubMed:22498659, ECO:0000269|PubMed:23022146,
CC ECO:0000269|PubMed:667499, ECO:0000269|PubMed:9839677}.
CC -!- SUBUNIT: Monomer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:1176086}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom gland.
CC {ECO:0000305|PubMed:1176086}.
CC -!- MASS SPECTROMETRY: Mass=4885.6; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:22498659};
CC -!- TOXIC DOSE: LD(50) is 1.5 mg/kg by intravenous injection.
CC {ECO:0000269|PubMed:1176086}.
CC -!- TOXIC DOSE: LD(50) is 32.8 mg/kg by intraperitoneal injection into
CC mice. {ECO:0000269|PubMed:9839677}.
CC -!- PHARMACEUTICAL: Has high potential for use as an anticancer agent. In
CC vivo treatment with this protein significantly delays tumor
CC implantation, inhibits tumor growth and prolongs the lifespan of the
CC mice with melanoma tumors. It has also potent and specific toxicity
CC against tumor cell lines of aggressive mouse and human tumors, but low
CC cytotoxicity against non-tumoral cell lines. In addition, this protein
CC can act as a carrier capable of delivering DNA into replicating cells
CC with low cytotoxicity against normal proliferative cells
CC (PubMed:21062230, PubMed:22142367, and PubMed:21834748).
CC -!- MISCELLANEOUS: Has no hemolytic activity (PubMed:21386851,
CC PubMed:23022146). Has low harmful effects on normal mammal cells. Does
CC not show activity against the filamentous fungi A.fumigatus and
CC T.rubrum at concentrations up to 125 ug/mL (PubMed:23022146). Does not
CC directly affect voltage-gated sodium channels Nav1.1/SCN1A,
CC Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.4/SCN4A, Nav1.5/SCN5A and Nav1.6/SCN8A
CC (PubMed:17588630). {ECO:0000305|PubMed:17588630,
CC ECO:0000305|PubMed:21386851, ECO:0000305|PubMed:23022146}.
CC -!- SIMILARITY: Belongs to the crotamine-myotoxin family. {ECO:0000305}.
CC -!- CAUTION: The analgesic activity produced by crotamine in Mancin et al.,
CC 1998 may be a misinterpretation (PubMed:9839677). This activity is
CC probably due to the co-elution with the 14 amino acids crotalphine
CC peptide (AC P08878). In that article crotamine was purified uniquely by
CC gel filtration G-75. This single chromatographic step without going
CC through a RP-HPLC is not sufficient to separate crotamine from other
CC low molecular weight peptides such as the potent analgesic crotalphine
CC peptide. {ECO:0000305}.
CC -!- CAUTION: Studies have shown that crotamine is present in the venom of
CC certain specimens of C.durissus terrificus, and absent in others. This
CC is due to geographical variations (PubMed:10484745).
CC {ECO:0000305|PubMed:10484745}.
CC -!- WEB RESOURCE: Name=Wikipedia;
CC URL="https://en.wikipedia.org/wiki/Crotamine";
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DR EMBL; AF053075; AAC06241.1; -; mRNA.
DR EMBL; AF223946; AAF34910.1; -; Genomic_DNA.
DR EMBL; AF223947; AAF34911.1; -; Genomic_DNA.
DR PIR; A01735; CXRSMT.
DR PDB; 1H5O; NMR; -; A=23-64.
DR PDB; 1Z99; NMR; -; A=23-64.
DR PDBsum; 1H5O; -.
DR PDBsum; 1Z99; -.
DR AlphaFoldDB; Q9PWF3; -.
DR BMRB; Q9PWF3; -.
DR SMR; Q9PWF3; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0015459; F:potassium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR GO; GO:0042742; P:defense response to bacterium; IEA:UniProtKB-KW.
DR GO; GO:0050832; P:defense response to fungus; IEA:UniProtKB-KW.
DR GO; GO:0044564; P:envenomation resulting in occlusion of the pore of voltage-gated potassium channel in another organism; IDA:UniProtKB.
DR GO; GO:0031640; P:killing of cells of another organism; IEA:UniProtKB-KW.
DR Gene3D; 2.20.20.10; -; 1.
DR InterPro; IPR023355; Myo_ane_neurotoxin_sf.
DR InterPro; IPR000881; Myotoxin.
DR Pfam; PF00819; Myotoxins; 1.
DR PRINTS; PR00283; MYOTOXIN.
DR PROSITE; PS00459; MYOTOXINS_1; 1.
DR PROSITE; PS51345; MYOTOXINS_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antibiotic; Antimicrobial; Direct protein sequencing;
KW Disulfide bond; Fungicide; Ion channel impairing toxin; Myotoxin;
KW Neurotoxin; Pharmaceutical; Potassium channel impairing toxin; Secreted;
KW Signal; Toxin; Voltage-gated potassium channel impairing toxin.
FT SIGNAL 1..22
FT /evidence="ECO:0000269|PubMed:1176086"
FT CHAIN 23..64
FT /note="Crotamine"
FT /evidence="ECO:0000269|PubMed:1176086"
FT /id="PRO_0000035184"
FT MOTIF 24..40
FT /note="Nuclear localization signal"
FT MOTIF 49..61
FT /note="Nuclear localization signal"
FT SITE 23
FT /note="Involved in the interaction surface toward Kv"
FT /evidence="ECO:0000305"
FT SITE 24
FT /note="Involved in the interaction surface toward Kv"
FT /evidence="ECO:0000305"
FT SITE 55
FT /note="Involved in the interaction surface toward Kv"
FT /evidence="ECO:0000305"
FT SITE 56
FT /note="Involved in the interaction surface toward Kv"
FT /evidence="ECO:0000305"
FT DISULFID 26..58
FT /evidence="ECO:0000269|PubMed:12709056,
FT ECO:0000269|PubMed:16185738, ECO:0000312|PDB:1H5O,
FT ECO:0000312|PDB:1Z99"
FT DISULFID 33..52
FT /evidence="ECO:0000269|PubMed:12709056,
FT ECO:0000269|PubMed:16185738, ECO:0000312|PDB:1H5O,
FT ECO:0000312|PDB:1Z99"
FT DISULFID 40..59
FT /evidence="ECO:0000269|PubMed:12709056,
FT ECO:0000269|PubMed:16185738, ECO:0000312|PDB:1H5O,
FT ECO:0000312|PDB:1Z99"
FT HELIX 24..29
FT /evidence="ECO:0007829|PDB:1H5O"
FT STRAND 31..35
FT /evidence="ECO:0007829|PDB:1H5O"
FT HELIX 36..38
FT /evidence="ECO:0007829|PDB:1Z99"
FT STRAND 41..44
FT /evidence="ECO:0007829|PDB:1H5O"
FT STRAND 49..52
FT /evidence="ECO:0007829|PDB:1H5O"
FT STRAND 56..60
FT /evidence="ECO:0007829|PDB:1H5O"
SQ SEQUENCE 65 AA; 7519 MW; FD109153C5BCCE33 CRC64;
MKILYLLFAF LFLAFLSEPG NAYKQCHKKG GHCFPKEKIC LPPSSDFGKM DCRWRWKCCK
KGSGK
