Fig. 3: The VSD domain in SLC9C1 is most similar to VSD_IV from human Na_V1.7.

a, The SLC9C1 homodimer (side view), with the NHE transporter (grey), VSD domains (cyan), CNBD (brown), and the intracellular helices ICH1–ICH4 (orange) and ICH5–ICH7 (purple), with one protomer labelled (left). Right, as described for the left image, but the extracellular view with the distance between the NHE and VSD domains labelled. b, Cartoon of one protomer as in a, and the other protomer as a surface representation (grey) highlighting the domain-swapped ICH1–ICH2 helices. c, Superimposition of the SLC9C1 VSD (cyan) with VSD_IV from Na_V1.7 (PDB: 7XMG; light pink, root mean squared deviation (r.m.s.d.) of 2.4 Å) and with the distal end of S4 omitted for clarity (top), and with VSD from the HCN channel (PDB: 5U6P; dark pink, r.m.s.d of 5.4 Å), shown as above, but with the entire S4 helix (bottom). d, VSD of SLC9C1 with S3 omitted to highlight key residues (yellow sticks) (left). The occlusion-forming Tyr743 in S2 and the negatively charged residue Glu746, together with Asp767, make up the conserved charge transfer centre⁴³. S4 is in the up-state and gating-charge residues Arg803 (R2) to Lys815 (K6) extend from the 3₁₀ helix. The gating-charge residues Arg803 (R2), Arg806 (R3) and Arg809 (R4) are positioned above the charge transfer centre, and probably account for the three measured gating-charges². Right, as described for the left image, with key residues of SLC9C1 (yellow sticks) and VSD_IV of human Na_V1.7 (pink sticks) labelled. e, The VSD from SLC9C1 (cyan) and a semi-transparent surface representation of ICH3–ICH4 (orange) and ICH5–ICH6 (purple) form extensive contacts to extramembranous S4 and the CNBD (brown). f, A 45° rotation of the VSD shown in e (all cartoon representation) and the S1 linker with the 9CA and 9CB helices are also highlighted. g, Cartoon of the VSD and ICH network (coloured as described in a) as viewed from the extracellular side with the NHE transporter module omitted (top). Bottom, as described for the top image, but one protomer is rendered in grey.