| Structural highlights
Function
MYC2_CRODU Cationic peptide that possesses multiple functions. It acts as a cell-penetrating peptide (CPP), and as a potent voltage-gated potassium channel inhibitor. It exhibits antimicrobial activities, hind limb paralysis, and severe muscle necrosis by a non-enzymatic mechanism. As a cell-penetrating peptide, crotamine has high specificity for actively proliferating cells, and interacts inside the cell with subcellular and subnuclear structures, like vesicular compartments, chromosomes and centrioles. It penetrates into the cells as fast as five minutes after its addition to cell culture medium (PubMed:18662711). In vivo, after intraperitoneal administration, it is found in cells of peritoneal fluid and bone marrow, demonstrating preferential nuclear and perinuclear localization. To enter the cell, it interacts with the chains of heparan sulfate membrane proteoglycan (HSPG), and is endocytosed (in complex with HSPG) in vesicles which are transported into the cell with the help of clathrin. Inside the cell, crotamine accumulates in lysosomal vesicles. As soon as the peptide accumulates in endosomes/lysosomes vesicles, these compartments are disrupted and their contents released into the cytosol. This loss of lysosomal content induces cell death at high concentrations, or promotes the distribution of crotamine in cytoplasmic compartments, which is a step before crotamine nuclear uptake (PubMed:15231729, PubMed:17491023). As a potassium channel inhibitor, this toxin selectively inhibits Kv1.1/KCNA1, Kv1.2/KCNA2 and Kv1.3/KCNA3 channels with an IC(50) of 369, 386 and 287 nM, respectively (PubMed:22498659). The inhibition of Kv1.3/KCNA channels induced by this toxin occurs rapidly and is voltage-independent. The channel inhibition is reversible after washing, suggesting a pure and classical channel blockage effect, without effects in potassium channel kinetics (PubMed:22498659). As an antimicrobial peptide, crotamine shows antibacterial activity against E.coli and B.subtilis, and antifungal activity against Candida spp., Trichosporon spp. and C.neoformans. It kills bacteria through membrane permeabilization.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
The crystal structure of the myotoxic, cell-penetrating, basic polypeptide crotamine isolated from the venom of Crotalus durissus terrificus has been determined by single-wavelength anomalous dispersion techniques and refined at 1.7 A resolution. The structure reveals distinct cationic and hydrophobic surface regions that are located on opposite sides of the molecule. This surface-charge distribution indicates its possible mode of interaction with negatively charged phospholipids and other molecular targets to account for its diverse pharmacological activities. Although the sequence identity between crotamine and human beta-defensins is low, the three-dimensional structures of these functionally related peptides are similar. Since crotamine is a leading member of a large family of myotoxic peptides, its structure will provide a basis for the design of novel cell-penetrating molecules.
Structure of the polypeptide crotamine from the Brazilian rattlesnake Crotalus durissus terrificus.,Coronado MA, Gabdulkhakov A, Georgieva D, Sankaran B, Murakami MT, Arni RK, Betzel C Acta Crystallogr D Biol Crystallogr. 2013 Oct;69(Pt 10):1958-64. doi:, 10.1107/S0907444913018003. Epub 2013 Sep 20. PMID:24100315[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Laure CJ. [The primary structure of crotamine (author's transl)]. Hoppe Seylers Z Physiol Chem. 1975 Feb;356(2):213-5. PMID:1176086
- ↑ Kerkis A, Kerkis I, Radis-Baptista G, Oliveira EB, Vianna-Morgante AM, Pereira LV, Yamane T. Crotamine is a novel cell-penetrating protein from the venom of rattlesnake Crotalus durissus terrificus. FASEB J. 2004 Sep;18(12):1407-9. doi: 10.1096/fj.03-1459fje. Epub 2004 Jul 1. PMID:15231729 doi:http://dx.doi.org/10.1096/fj.03-1459fje
- ↑ Nascimento FD, Hayashi MA, Kerkis A, Oliveira V, Oliveira EB, Radis-Baptista G, Nader HB, Yamane T, Tersariol IL, Kerkis I. Crotamine mediates gene delivery into cells through the binding to heparan sulfate proteoglycans. J Biol Chem. 2007 Jul 20;282(29):21349-60. doi: 10.1074/jbc.M604876200. Epub 2007, May 9. PMID:17491023 doi:http://dx.doi.org/10.1074/jbc.M604876200
- ↑ Rizzi CT, Carvalho-de-Souza JL, Schiavon E, Cassola AC, Wanke E, Troncone LR. Crotamine inhibits preferentially fast-twitching muscles but is inactive on sodium channels. Toxicon. 2007 Sep 15;50(4):553-62. doi: 10.1016/j.toxicon.2007.04.026. Epub 2007 , May 18. PMID:17588630 doi:http://dx.doi.org/10.1016/j.toxicon.2007.04.026
- ↑ Hayashi MA, Nascimento FD, Kerkis A, Oliveira V, Oliveira EB, Pereira A, Radis-Baptista G, Nader HB, Yamane T, Kerkis I, Tersariol IL. Cytotoxic effects of crotamine are mediated through lysosomal membrane permeabilization. Toxicon. 2008 Sep 1;52(3):508-17. doi: 10.1016/j.toxicon.2008.06.029. Epub 2008, Jul 10. PMID:18662711 doi:http://dx.doi.org/10.1016/j.toxicon.2008.06.029
- ↑ Yount NY, Kupferwasser D, Spisni A, Dutz SM, Ramjan ZH, Sharma S, Waring AJ, Yeaman MR. Selective reciprocity in antimicrobial activity versus cytotoxicity of hBD-2 and crotamine. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14972-7. doi:, 10.1073/pnas.0904465106. Epub 2009 Aug 13. PMID:19706485 doi:http://dx.doi.org/10.1073/pnas.0904465106
- ↑ Oguiura N, Boni-Mitake M, Affonso R, Zhang G. In vitro antibacterial and hemolytic activities of crotamine, a small basic myotoxin from rattlesnake Crotalus durissus. J Antibiot (Tokyo). 2011 Apr;64(4):327-31. doi: 10.1038/ja.2011.10. Epub 2011 Mar, 9. PMID:21386851 doi:http://dx.doi.org/10.1038/ja.2011.10
- ↑ Nascimento FD, Sancey L, Pereira A, Rome C, Oliveira V, Oliveira EB, Nader HB, Yamane T, Kerkis I, Tersariol IL, Coll JL, Hayashi MA. The natural cell-penetrating peptide crotamine targets tumor tissue in vivo and triggers a lethal calcium-dependent pathway in cultured cells. Mol Pharm. 2012 Feb 6;9(2):211-21. doi: 10.1021/mp2000605. Epub 2011 Dec 23. PMID:22142367 doi:http://dx.doi.org/10.1021/mp2000605
- ↑ Peigneur S, Orts DJ, Prieto da Silva AR, Oguiura N, Boni-Mitake M, de Oliveira EB, Zaharenko AJ, de Freitas JC, Tytgat J. Crotamine pharmacology revisited: novel insights based on the inhibition of KV channels. Mol Pharmacol. 2012 Jul;82(1):90-6. doi: 10.1124/mol.112.078188. Epub 2012 Apr, 12. PMID:22498659 doi:http://dx.doi.org/10.1124/mol.112.078188
- ↑ Yamane ES, Bizerra FC, Oliveira EB, Moreira JT, Rajabi M, Nunes GL, de Souza AO, da Silva ID, Yamane T, Karpel RL, Silva PI Jr, Hayashi MA. Unraveling the antifungal activity of a South American rattlesnake toxin crotamine. Biochimie. 2013 Feb;95(2):231-40. doi: 10.1016/j.biochi.2012.09.019. Epub 2012, Sep 26. PMID:23022146 doi:http://dx.doi.org/10.1016/j.biochi.2012.09.019
- ↑ Chang CC, Tseng KH. Effect of crotamine, a toxin of South American rattlesnake venom, on the sodium channel of murine skeletal muscle. Br J Pharmacol. 1978 Jul;63(3):551-9. doi: 10.1111/j.1476-5381.1978.tb07811.x. PMID:667499 doi:http://dx.doi.org/10.1111/j.1476-5381.1978.tb07811.x
- ↑ Mancin AC, Soares AM, Andriao-Escarso SH, Faca VM, Greene LJ, Zuccolotto S, Pela IR, Giglio JR. The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: a biochemical and pharmacological study. Toxicon. 1998 Dec;36(12):1927-37. PMID:9839677
- ↑ Coronado MA, Gabdulkhakov A, Georgieva D, Sankaran B, Murakami MT, Arni RK, Betzel C. Structure of the polypeptide crotamine from the Brazilian rattlesnake Crotalus durissus terrificus. Acta Crystallogr D Biol Crystallogr. 2013 Oct;69(Pt 10):1958-64. doi:, 10.1107/S0907444913018003. Epub 2013 Sep 20. PMID:24100315 doi:http://dx.doi.org/10.1107/S0907444913018003
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