2qog

Structural highlights

Function

[PA2BA_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] Monomer CBa2: The basic subunit of crotoxin is a snake venom phospholipase A2 (PLA2) that exhibits weak neurotoxicity (10-fold less than the heterodimer) and strong anticoagulant effects by binding to factor Xa (F10) and inhibiting the prothrombinase activity (IC(50) is 41 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.^[2] [PA2BC_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).^[3] 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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Phospholipase A2

References

1. ↑ 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
2. ↑ 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
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. ↑ 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
5. ↑ Marchi-Salvador DP, Correa LC, Magro AJ, Oliveira CZ, Soares AM, Fontes MR. Insights into the role of oligomeric state on the biological activities of crotoxin: Crystal structure of a tetrameric phospholipase A(2) formed by two isoforms of crotoxin B from Crotalus durissus terrificus venom. Proteins. 2008 Feb 14;. PMID:18275084 doi:10.1002/prot.21980