3r0l

Structural highlights

Function

[PA2B_CRODU] 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) 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. 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).^{[1] [2] [3]} [REFERENCE:12] Monomer CBc: The basic subunit of crotoxin is a snake venom phospholipase A2 (PLA2) that exhibits weak neurotoxicity (10-fold less than the heterodimer) and very strong anticoagulant effects by binding to factor Xa (F10) and inhibiting the prothrombinase activity (IC(50) is 0.7 nM) (PubMed:18062812). In addition, it shows the same effects described for the heterodimer and binds the nucleotide-binding domain (NBD1) of CFTR chloride channels and increases the channel current. PLA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides.^{[4] [5] [6]} [REFERENCE:12]

References

1. ↑ Chen YH, Wang YM, Hseu MJ, Tsai IH. Molecular evolution and structure-function relationships of crotoxin-like and asparagine-6-containing phospholipases A2 in pit viper venoms. Biochem J. 2004 Jul 1;381(Pt 1):25-34. PMID:15032748 doi:http://dx.doi.org/10.1042/BJ20040125
2. ↑ Donato NJ, Martin CA, Perez M, Newman RA, Vidal JC, Etcheverry M. Regulation of epidermal growth factor receptor activity by crotoxin, a snake venom phospholipase A2 toxin. A novel growth inhibitory mechanism. Biochem Pharmacol. 1996 Jun 14;51(11):1535-43. PMID:8630095
3. ↑ Faure G, Gowda VT, Maroun RC. Characterization of a human coagulation factor Xa-binding site on Viperidae snake venom phospholipases A2 by affinity binding studies and molecular bioinformatics. BMC Struct Biol. 2007 Dec 6;7:82. PMID:18062812 doi:http://dx.doi.org/10.1186/1472-6807-7-82
4. ↑ Chen YH, Wang YM, Hseu MJ, Tsai IH. Molecular evolution and structure-function relationships of crotoxin-like and asparagine-6-containing phospholipases A2 in pit viper venoms. Biochem J. 2004 Jul 1;381(Pt 1):25-34. PMID:15032748 doi:http://dx.doi.org/10.1042/BJ20040125
5. ↑ Donato NJ, Martin CA, Perez M, Newman RA, Vidal JC, Etcheverry M. Regulation of epidermal growth factor receptor activity by crotoxin, a snake venom phospholipase A2 toxin. A novel growth inhibitory mechanism. Biochem Pharmacol. 1996 Jun 14;51(11):1535-43. PMID:8630095
6. ↑ Faure G, Gowda VT, Maroun RC. Characterization of a human coagulation factor Xa-binding site on Viperidae snake venom phospholipases A2 by affinity binding studies and molecular bioinformatics. BMC Struct Biol. 2007 Dec 6;7:82. PMID:18062812 doi:http://dx.doi.org/10.1186/1472-6807-7-82
7. ↑ 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