Modular organization of α-toxins from scorpion venom mirrors domain structure of their targets, sodium channels.
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 (Na(v)s) and thereby modify the excitability of muscle and nerve cells. Although more than 100 α-toxins are known and a number of them have been studied into detail, the molecular mechanism of their interaction with Na(v)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 despite 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 versus 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 the extracellular loops of Na(v)s suggests that α-toxins recognize the channels using both modules. We propose that the core module binds to the voltage-sensing domain IV, whereas the more versatile SM interacts with the pore domain in repeat I of Na(v)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 Na(v)s.
['Chugunov|Anton O|AO|', 'Koromyslova|Anna D|AD|', 'Berkut|Antonina A|AA|', 'Peigneur|Steve|S|', 'Tytgat|Jan|J|', 'Polyansky|Anton A|AA|', 'Pentkovsky|Vladimir M|VM|', 'Vassilevski|Alexander A|AA|', 'Grishin|Eugene V|EV|', 'Efremov|Roman G|RG|']
D000595:Amino Acid Sequence D000818:Animals D019295:Computational Biology D003198:Computer Simulation D057927:Hydrophobic and Hydrophilic Interactions D008969:Molecular Sequence Data D009498:Neurotoxins D025941:Protein Interaction Mapping D017433:Protein Structure, Secondary D017434:Protein Structure, Tertiary D011994:Recombinant Proteins D012604:Scorpion Venoms D017386:Sequence Homology, Amino Acid D015222:Sodium Channels D013329:Structure-Activity Relationship D013499:Surface Properties
Sodium Channels Neurotoxin Molecular Dynamics Ion Channels Membrane Proteins Protein Domains Protein Dynamics Protein Structure Protein-Protein Interactions