Figure S1.
Conservation of the speed-control residue in the S2 segment in different types of fast and slowly activating NaV channels and slowly activating KV channels. The residues homologous to Shaker I287 are marked in red if hydrophobic (E and D) and in blue if hydrophilic (I, V, and M). The data clearly show that in the first three domains of all the reported fast-activating Na channels the position homologous to Shaker I287 is occupied by a threonine residue, confirming the functional importance of the hydrophilic threonine at this position. The IV domain of fast-activating NaV channels shows instead either an isoleucine or a valine at the corresponding position, in accordance with a functional role of this domain not primarily involved in the activation but in the slower inactivation process. As for the slowly activating bacterial Na channels, hydrophobic isoleucine or leucine is found, again in accordance with a direct correspondence between the hydrophilicity of this residue and the rate of voltage sensor activation. Finally, as in Shaker channels, also in KvAP and the 31 members of the first 9 families of human KV channels, the position homologous to Shaker I287 is occupied by a hydrophobic residue (isoleucine to valine, methionine in one case), thus strengthening the notion of a strict association between the slow voltage activation of KV channels and the presence of a hydrophobic residue at this position. This association is instead not respected in the last three families of KV channels (EAG or Kv10, ERG or Kv11, and ELK or Kv12), where a negatively charged residue at the position homologous to Shaker I287 is always found. Although we do not have a clear explanation for this finding, it is interesting to see that for these groups of KV channels, a different interdomain assembly, with a nonswapped topology between VSD and pore domain, has been found (Butler et al., 2020; Wang and MacKinnon, 2017; Whicher and MacKinnon, 2016). It is also interesting that MTSET accessibility data indicate that in human ERG KV channels the extracellular water crevice enters into the VSD well beyond the residue D460 (homologous to Shaker I287) and F463 (homologous to Shaker F290). Thus, the organization of the VSD in these channels appears markedly different as compared with the KV channels with a swapped-domain topology, of interest in our study.

Conservation of the speed-control residue in the S2 segment in different types of fast and slowly activating NaV channels and slowly activating KV channels. The residues homologous to Shaker I287 are marked in red if hydrophobic (E and D) and in blue if hydrophilic (I, V, and M). The data clearly show that in the first three domains of all the reported fast-activating Na channels the position homologous to Shaker I287 is occupied by a threonine residue, confirming the functional importance of the hydrophilic threonine at this position. The IV domain of fast-activating NaV channels shows instead either an isoleucine or a valine at the corresponding position, in accordance with a functional role of this domain not primarily involved in the activation but in the slower inactivation process. As for the slowly activating bacterial Na channels, hydrophobic isoleucine or leucine is found, again in accordance with a direct correspondence between the hydrophilicity of this residue and the rate of voltage sensor activation. Finally, as in Shaker channels, also in KvAP and the 31 members of the first 9 families of human KV channels, the position homologous to Shaker I287 is occupied by a hydrophobic residue (isoleucine to valine, methionine in one case), thus strengthening the notion of a strict association between the slow voltage activation of KV channels and the presence of a hydrophobic residue at this position. This association is instead not respected in the last three families of KV channels (EAG or Kv10, ERG or Kv11, and ELK or Kv12), where a negatively charged residue at the position homologous to Shaker I287 is always found. Although we do not have a clear explanation for this finding, it is interesting to see that for these groups of KV channels, a different interdomain assembly, with a nonswapped topology between VSD and pore domain, has been found (Butler et al., 2020; Wang and MacKinnon, 2017; Whicher and MacKinnon, 2016). It is also interesting that MTSET accessibility data indicate that in human ERG KV channels the extracellular water crevice enters into the VSD well beyond the residue D460 (homologous to Shaker I287) and F463 (homologous to Shaker F290). Thus, the organization of the VSD in these channels appears markedly different as compared with the KV channels with a swapped-domain topology, of interest in our study.

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