3g8h

Structural highlights

Function

PA2BC_VIPAA Snake venom phospholipase A2 (PLA2) that acts as a presynaptic neurotoxin, an inhibitor of blood coagulation, and has been found to bind with high affinity to intracellular proteins. The response of indirectly stimulated neuromuscular preparations to ammodytoxin (Atx) is triphasic. The first phase, the transient inhibition of the acetylcholine (ACh) release, starts soon after the addition of Atx and lasts for several minutes. This phase is probably independent of Atx enzymatic activity. The effect may be due to the specific binding of the toxin to presynaptic receptors. These receptors, called N-type receptors, are still unidentified. It is noteworthy that a neuronal isoform of the M-type PLA2 receptor (R180) has been identified as a high-affinity receptor for Atx in neuronal plasma membranes. It was demonstrated however that this receptor is not essential for expression of neurotoxicity by Atx. The second phase corresponds to an augmentation of neurotransmitter release. A peak is reached 10-20 min after exposure of the preparation to Atx and is followed by a gradual reduction. In this phase, the enzymatic activity of Atx of the mammalian is not significant. It is speculated that the increased release of neurotransmitter in this phase is induced by the interference of Atx with voltage-gated potassium channels. Measurements of ionic showed however that voltage-gated potassium channels are not affected by Atx. The third phase of the response of neuromuscular preparations to Atx, which corresponds to a complete and irreversible paralysis, is clearly dependent on the hydrolytic activity of the toxin. In addition to its presynaptic neurotoxicity, Atx shows an anticoagulant activity by binding with high affinity to activated coagulation factor X (F10) thus inhibiting the formation of the prothrombinase complex (FX/FV) and its activity (IC(50) is 240 nM). Surprisingly, Atx was discovered to bind intracellular proteins such as calmodulin (CaM), 14-3-3 proteins gamma (YWHAG) and epsilon (YWHAE), as well as R25, a mitochondrial integral membrane protein found in cerebral cortex. These findings raised a doubt about the dogma of the exclusively extracellular action of PLA2s, defended by the potential instability of these molecules in the reducing environment of the eukaryotic cytosol coupled with their possible inability to act as enzymes in this cellular compartment, due to too low concentration of calcium ions. This hypothesis was challenged efficiently by demonstrating the internalization of AtxA into a culture cells, but still remains to be directly demonstrated in vivo (By similarity). PLA2 catalyzes the calcium-dependent hydrolysis of the 2-acyl groups in 3-sn-phosphoglycerides.^{[1] [2] [3]}

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 3D structures

References

1. ↑ Fathi H B, Rowan EG, Harvey AL. The facilitatory actions of snake venom phospholipase A(2) neurotoxins at the neuromuscular junction are not mediated through voltage-gated K(+) channels. Toxicon. 2001 Dec;39(12):1871-82. PMID:11600150
2. ↑ Petan T, Krizaj I, Gelb MH, Pungercar J. Ammodytoxins, potent presynaptic neurotoxins, are also highly efficient phospholipase A2 enzymes. Biochemistry. 2005 Sep 20;44(37):12535-45. PMID:16156665 doi:http://dx.doi.org/10.1021/bi051024r
3. ↑ Prijatelj P, Charnay M, Ivanovski G, Jenko Z, Pungercar J, Krizaj I, Faure G. The C-terminal and beta-wing regions of ammodytoxin A, a neurotoxic phospholipase A2 from Vipera ammodytes ammodytes, are critical for binding to factor Xa and for anticoagulant effect. Biochimie. 2006 Jan;88(1):69-76. Epub 2005 Jul 7. PMID:16039772 doi:http://dx.doi.org/10.1016/j.biochi.2005.06.015
4. ↑ Saul FA, Prijatelj-Znidarsic P, Vulliez-le Normand B, Villette B, Raynal B, Pungercar J, Krizaj I, Faure G. Comparative structural studies of two natural isoforms of ammodytoxin, phospholipases A2 from Vipera ammodytes ammodytes which differ in neurotoxicity and anticoagulant activity. J Struct Biol. 2010 Mar;169(3):360-9. Epub 2009 Oct 24. PMID:19857576 doi:10.1016/j.jsb.2009.10.010