The role of crotoxin subunits in tropical rattlesnake neurotoxic action

Hendon, R.A.; Tu, Anthony T.

doi:10.1016/0005-2795(79)90132-6

Cited by 41 publications

(7 citation statements)

References 17 publications

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“…This mechanism of dissociation is necessary for exhibiting the lethal potency of crotoxin, since covalent linkage between the two subunits abolishes toxicity. 32 Thus, the CA and CB subunits of crotoxin act in a synergistic manner. In the case of the more toxic crotoxin complexes, the nontoxic CA subunit enhances the toxicity of CB and reduces its enzymatic and anticoagulant activities.…”

Section: Introductionmentioning

confidence: 98%

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

Faure¹,

Xu²,

Saul³

2011

Journal of Molecular Biology

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Section: Introductionmentioning

confidence: 98%

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

Faure¹,

Xu²,

Saul³

2011

Journal of Molecular Biology

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“…This, together with the finding that crotoxin PLA increased the binding of crotapotin, suggests that crotoxin binds with its target in a complex form though thenceforth crotapotin may dissociate leaving crotoxin PLA alone at the site. Hendon & Tu (1979) found that, after crosslinkage of crotoxin PLA and crotapotin with a bifunctional cross-linking agent, the non-dissociable crotoxin was much less lethal than the dissociable crotoxin although the enzyme activity was not reduced. This result was taken to suggest that, for crotoxin PLA to be able to bind, crotapotin has to dissociate first.…”

Section: Discussionmentioning

confidence: 99%

A STUDY ON THE INTERACTION OF CROTAPOTIN WITH CROTOXIN PHOSPHOLIPASE A₂, NOTEXIN AND OTHER PRESYNAPTIC NEUROTOXINS

Chang

1981

British J Pharmacology

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1 Crotapotin, the acidic subunit of crotoxin, greatly potentiated the presynaptic effect of isolated basic phospholipase A (PLA) of crotoxin in both mouse diaphragm and chick biventer cervicis muscles whereas the myotoxic effect was not affected significantly. 2 In contrast to crotoxin PLA, the presynaptic effects of notexin and notechis-5, self-active single chain toxins, were antagonized by crotapotin while actions of 3-bungarotoxin were not affected. 3 By assaying PLA activity, crotoxin PLA was found to be unstable in physiological salt solution, especially when in contact with muscle, due to massive non-specific binding to and destruction by the muscle. 4 The decline of crotoxin PLA was greatly reduced by the presence of crotapotin but not by another acidic protein, volvatoxin A2, or heparin. 5 Notechis-5 was found to be stable even when in the presence of muscles. 6[3H]-acetylated crotoxin PLA, which retained about 40o of its original enzyme and presynaptic blocking activities, also bound rapidly to the mouse diaphragm on incubation and this binding was greatly hindered by the simultaneous addition of crotapotin. 7 The prevention of binding of crotoxin PLA by crotapotin occurred mostly at those sites where the binding was easily dissociable on washing. No antagonism of binding occurred at the firmly binding site.8 The binding of [3H]-acetylated crotapotin was much less than that of crotoxin PLA, and interestingly, the binding was increased by the latter, suggesting that crotapotin may be first bound to the diaphragm together with crotoxin PLA. 9 No specific binding at the endplate zone was found either for crotoxin PLA or for crotapotin. 10 It is concluded that crotapotin potentiates the presynaptic effect of crotoxin PLA by curtailing its non-specific affinity with muscles, minimizing its dispersal and destruction en route to the nerve terminal, but not by acting as an affinity probe for the nerve terminal.

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“…It has been proposed that the 'chaperonic' subunit may participate in the formation of a transient ternary complex with PLA 2 and the acceptor targeting the enzyme onto the membrane acceptor and increasing its pharmacological activity [47]. The covalent linkage of the subunits by a bifunctional reagent does not reduce the enzymatic activity but completely abolishes the lethal potency of crotoxin [48]. Immunological studies with monoclonal antibodies allowed characterization of epitopic regions on both subunits with respect to 'toxic' and 'catalytic' sites in PLA 2 [49].…”

Section: Oligomeric Snake Venom Neurotoxinsmentioning

confidence: 99%

Modulation of phospholipase A 2 activity generated by molecular evolution

Betzel

Genov

Rajashankar

et al. 1999

Cellular and Molecular Life Sciences (CMLS)

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Snake venom oligomeric neurotoxins offer several unique examples of modulation of phospholipase A2 (PLA2) activity generated by molecular evolution. This phenomenon was found in evolutionary younger snakes and is probably common for representatives of the genus Vipera. At present, the best-studied example is the heterodimeric neurotoxin vipoxin from the venom of the southeast European snake Vipera ammodytes meridionalis. It is a complex between a basic strongly toxic PLA2 and an acidic and catalytically inactive PLA2-like component (Inh). This is the first reported example of a high degree of structural homology (62%) between an enzyme and its natural protein inhibitor. The inhibitor is a product of the divergent evolution of the unstable PLA2 in order to stabilize it and to preserve the pharmacological activity/toxicity for a long time. Inh reduces both the catalytic activity and toxicity of PLA2. Vipoxin also illustrates evolution of the catalytic into a inhibitory function. Vipoxin analogues have been found in the venom of viperid snakes inhabiting diverse regions of the world. An attempt is made to explain modulation of the toxic function by the three-dimensional structure of vipoxin.

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The role of crotoxin subunits in tropical rattlesnake neurotoxic action

Cited by 41 publications

References 17 publications

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

A STUDY ON THE INTERACTION OF CROTAPOTIN WITH CROTOXIN PHOSPHOLIPASE A₂, NOTEXIN AND OTHER PRESYNAPTIC NEUROTOXINS

Modulation of phospholipase A 2 activity generated by molecular evolution

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The role of crotoxin subunits in tropical rattlesnake neurotoxic action

Cited by 41 publications

References 17 publications

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

A STUDY ON THE INTERACTION OF CROTAPOTIN WITH CROTOXIN PHOSPHOLIPASE A2, NOTEXIN AND OTHER PRESYNAPTIC NEUROTOXINS

Modulation of phospholipase A 2 activity generated by molecular evolution

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A STUDY ON THE INTERACTION OF CROTAPOTIN WITH CROTOXIN PHOSPHOLIPASE A₂, NOTEXIN AND OTHER PRESYNAPTIC NEUROTOXINS