3r0l

Structural highlights

Function

PA2H_CRODU CAalpha-CAbeta-CAgamma: The acidic subunit of crotoxin (CA) is a heterotrimer of three disulfide-linked chains generated by post-translational maturation of a PLA2-like precursor. CA has no PLA2 activity and is not neurotoxic by itself, but plays several important functions in the crotoxin complex by increasing the lethal potency of the uncomplexed CB subunit. It acts by physically occluding the hydrophobic interfacial binding surface (IBS) of CB (PubMed:21787789, PubMed:21787789). This effect decreases the adsorption of CB to phospholipid membranes, targeting the crotoxin complex to reach the specific presynaptic receptor (R48) at the neuromuscular junction. It also prevents the formation of the reactive CB dimer. Moreover, the CA subunit inhibits the catalytic activity by partially masking the catalytic site of CB (PubMed:21787789) and inhibits its anticoagulant activity.^[1] Heterodimer CA-CB: Crotoxin is a potent presynaptic neurotoxin that possesses phospholipase A2 (PLA2) activity and exerts a lethal action by blocking neuromuscular transmission. It consists of a non-covalent association of a basic and weakly toxic PLA2 subunit (CBa2, CBb, CBc, or CBd), with a small acidic, non-enzymatic and non-toxic subunit (CA1, CA2, CA3 or CA4). The complex acts by binding to a specific 48-kDa protein (R48/CAPT) receptor located on presynaptic membranes, forming a transient ternary complex CA-CB-R48, followed by dissociation of the CA-CB complex and release of the CA subunit (PubMed:12657321). At equilibrium, only the CB subunits remain associated with the specific crotoxin receptor. In addition to neurotoxicity, crotoxin has been found to exert myotoxicity, nephrotoxicity, and cardiovascular toxicity (PubMed:20109480). Moreover, anti-inflammatory, immunomodulatory, anti-tumor and analgesic effects of crotoxin have also been reported (PubMed:20109480).^{[2] [3]} Found in the venom as a monomer and stabilized by one disulfide bond (Cys-131 and Cys-138) (PubMed:18495297). This peptide induces potent antinociceptive effects in acute and chronic pain models (PubMed:18495297, PubMed:18703042). This effect is mediated by the release of peripheral dynorphin A, an endogenous agonist of kappa-opioid receptors, and this release is dependent on cannabinoid receptor CB2 activation (PubMed:24460677).^{[4] [5] [6]}

References

1. ↑ Faure G, Xu H, Saul FA. Crystal structure of crotoxin reveals key residues involved in the stability and toxicity of this potent heterodimeric beta-neurotoxin. J Mol Biol. 2011 Sep 16;412(2):176-91. Epub 2011 Jul 23. PMID:21787789 doi:10.1016/j.jmb.2011.07.027
2. ↑ Faure G, Copic A, Le Porrier S, Gubensek F, Bon C, Krizaj I. Crotoxin acceptor protein isolated from Torpedo electric organ: binding properties to crotoxin by surface plasmon resonance. Toxicon. 2003 Mar;41(4):509-17. PMID:12657321
3. ↑ Sampaio SC, Hyslop S, Fontes MR, Prado-Franceschi J, Zambelli VO, Magro AJ, Brigatte P, Gutierrez VP, Cury Y. Crotoxin: novel activities for a classic beta-neurotoxin. Toxicon. 2010 Jun 1;55(6):1045-60. doi: 10.1016/j.toxicon.2010.01.011. Epub 2010 , Jan 28. PMID:20109480 doi:http://dx.doi.org/10.1016/j.toxicon.2010.01.011
4. ↑ Konno K, Picolo G, Gutierrez VP, Brigatte P, Zambelli VO, Camargo AC, Cury Y. Crotalphine, a novel potent analgesic peptide from the venom of the South American rattlesnake Crotalus durissus terrificus. Peptides. 2008 Aug;29(8):1293-304. doi: 10.1016/j.peptides.2008.04.003. Epub 2008, May 20. PMID:18495297 doi:http://dx.doi.org/10.1016/j.peptides.2008.04.003
5. ↑ Gutierrez VP, Konno K, Chacur M, Sampaio SC, Picolo G, Brigatte P, Zambelli VO, Cury Y. Crotalphine induces potent antinociception in neuropathic pain by acting at peripheral opioid receptors. Eur J Pharmacol. 2008 Oct 10;594(1-3):84-92. doi: 10.1016/j.ejphar.2008.07.053., Epub 2008 Jul 31. PMID:18703042 doi:http://dx.doi.org/10.1016/j.ejphar.2008.07.053
6. ↑ Machado FC, Zambelli VO, Fernandes AC, Heimann AS, Cury Y, Picolo G. Peripheral interactions between cannabinoid and opioid systems contribute to the antinociceptive effect of crotalphine. Br J Pharmacol. 2014 Feb;171(4):961-72. PMID:24460677 doi:10.1111/bph.12488