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Solution structure of Crotamine, a neurotoxin from Crotalus durissus terrificusSolution structure of Crotamine, a neurotoxin from Crotalus durissus terrificus
Structural highlights
FunctionMYC2_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] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCrotamine is a component of the venom of the snake Crotalus durissus terrificus and it belongs to the myotoxin protein family. It is a 42 amino acid toxin cross-linked by three disulfide bridges and characterized by a mild toxicity (LD50 = 820 micro g per 25 g body weight, i.p. injection) when compared to other members of the same family. Nonetheless, it possesses a wide spectrum of biological functions. In fact, besides being able to specifically modify voltage-sensitive Na+ channel, it has been suggested to exhibit analgesic activity and to be myonecrotic. Here we report its solution structure determined by proton NMR spectroscopy. The secondary structure comprises a short N-terminal alpha-helix and a small antiparallel triple-stranded beta-sheet arranged in an alphabeta1beta2beta3 topology never found among toxins active on ion channels. Interestingly, some scorpion toxins characterized by a biological activity on Na+ channels similar to the one reported for crotamine, exhibit an alpha/beta fold, though with a beta1alphabeta2beta3 topology. In addition, as the antibacterial beta-defensins, crotamine interacts with lipid membranes. A comparison of crotamine with human beta-defensins shows a similar fold and a comparable net positive potential surface. To the best of our knowledge, this is the first report on the structure of a toxin from snake venom active on Na+ channel. Solution structure of crotamine, a Na+ channel affecting toxin from Crotalus durissus terrificus venom.,Nicastro G, Franzoni L, de Chiara C, Mancin AC, Giglio JR, Spisni A Eur J Biochem. 2003 May;270(9):1969-79. PMID:12709056[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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