3-D structure of the voltage-sensing domain and creation of a gating pore. 3-D structure of the domain I VSD structure of WT (top) and mutated (R225W, bottom) NaV1.5 channels in a partially activated state (β state). The protein segments are shown in orange and the volume occupied by water in blue. The amino acids participating in the gating charge transfer center (GCTC) are shown as blue spheres for positive charges on the S4 segment, red for negative charges on the S2 and S3 segments, and green for positive charges on the S4 segment. A conserved aromatic amino acid is shown on the S2 segment. The left panels show the entire VSD, the S1 segment has been deleted in the middle, and right panels are shown for the sake of clarity. The middle panels highlight the close interactions between the positive charges on the S4 segment and the GCTC. These interactions allow the formation of a hydrophobic septum in the center of the VSD, isolating the water crevices on both sides of the membrane (right). In the context of a mutation (here, R225W), the interactions between S4 and GCTC are broken, causing the junction of the water crevices, creating a continuous aqueous pathway, and opening a gating pore (adapted from Moreau and Chahine, 2015).
