Allosteric interactions among voltage-sensor modules of sodium channels probed by scorpion toxin modifiers

Abstract

Gating of voltage-dependent sodium channels involves coordinated movements of the voltage sensors in the voltage-sensing modules (VSMs) of the four domains (DI-DIV) in response to membrane depolarization. Zhu et al. have recently examined the effects of charge reversal substitutions at the VSM of domain III on the action of scorpion alpha- and beta-toxins that intercept the voltage sensors in domains IV and II, respectively. The increased activity of both toxin types on the mutant channels has suggested that the VSM module at domain III interacts allosterically with the VSM modules in domains IV and II during channel gating thus affecting indirectly the action of both scorpion toxin classes.

Figure 1:. Motion transmission upon in-silico deactivation of voltage-sensing helix DIII-S4 in the cockroach sodium channel BgNav1–1a.

In the intermembrane (A) and extracellular (B) views, repeat domains I, II, III and IV are in pink, yellow, green and gray, respectively. The channel model with activated VSMs and presumably inactivated Pore module was computed at the Compute Canada (www.computecanada.ca) using the AlphaFold2 software [34]. Then the Pore module was in-silico opened towards the cryo-EM structure of the open rNav1.5 channel [35] and helix DIII-S4 was stepwise shifted in the cytoplasmic direction using described methods [29,36]. Twenty-one snapshots were superimposed with PyMol (Version 0.99rc6; Schrödinger, LLC, New York, NY). The forced downshift of helix DIII-S4 caused perturbations all over the channel. In particular, the shift was transmitted to the linker-helix DIII-S4-S5 and then to DII-VSM through hydrophobic contacts between DIII-S5 and DII-S4 (C). Helix DIV-S5 shifted down due to a hydrophobic contact with DIII-S4 (D), and through linker-helix DIV-S4-S5 the motion was transmitted to DIV-VSM.