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Статья

Chugunov A.O., Koromyslova A.D., Berkut A.A., Peigneur S., Tytgat J., Polyansky A.A., Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets - Sodium Channels

Journal of biological chemistry. 2013. Vol. 88. No. 26. P. 19014-19027.
Chugunov A. O., Koromyslova A. D., Berkut A. A., Peigneur S., Tytgat J., Polyansky A. A., Pentkovsky V. M., Vassilevski A. A., Grishin E. V., Efremov R.

To gain success in the evolutionary “arms race”, venomous animals such as scorpions produce diverse neurotoxins selected to hit targets in the nervous system of prey. Scorpion α-toxins affect insect and/or mammalian voltage-gated sodium channels (Nav’s) and thereby modify the excitability of muscle and nerve cells. Although more than a hundred α-toxins are known and a number of them have been studied into detail, the molecular mechanism of their interaction with Nav’s is still poorly understood. Here, we employ extensive molecular dynamics simulations and spatial mapping of hydrophobic/hydrophilic properties distributed over the molecular surface of α-toxins. It is revealed that in spite of the small size and relatively rigid structure, these toxins possess modular organization from structural, functional and evolutionary perspectives. The more conserved and rigid “core module” is supplemented with the “specificity module” (SM) that is comparatively flexible and variable, and determines the taxon (mammal vs. insect) specificity of α-toxin activity. We further show that SMs in mammal toxins are more flexible and hydrophilic than in insect toxins. Concomitant sequence-based analysis of Nav’s extracellular loops suggests that α-toxins recognize the channels using both modules. We propose that the core module binds to the voltage-sensing domain of repeat IV, whereas the more versatile SM interacts with the pore domain in repeat I of Nav’s. These findings corroborate and expand the hypothesis on different functional epitopes of toxins that has been reported previously. In effect, we propose that the modular structure in toxins evolved to match the domain architecture of Nav’s.