Trp207 regulation of voltage-dependent activation of human H_v1 proton channel

In voltage-gated Na⁺ and K⁺ channels, the hydrophobicity of noncharged residues in the S4 helix has been shown to regulate the S4 movement underlying the process of voltage-sensing domain (VSD) activation. In voltage-gated proton channel H_v1, there is a bulky noncharged tryptophan residue located at the S4 transmembrane segment. This tryptophan remains entirely conserved across all H_v1 members but is not seen in other voltage-gated ion channels, indicating that the tryptophan contributes different roles in VSD activation. The conserved tryptophan of human voltage-gated proton channel H_v1 is Trp207 (W207). Here, we showed that W207 modifies human H_v1 voltage-dependent activation, and small residues replacement at position 207 strongly perturbs H_v1 channel opening and closing, and the size of the side chain instead of the hydrophobic group of W207 regulates the transition between closed and open states of the channel. We conclude that the large side chain of tryptophan controls the energy barrier during the H_v1 VSD transition.