Fig. 7.

Differences in IQ motif binding between Na_v1.5 and Na_v1.4. The structures were superposed based on Na_V CT helix 6, containing the IQ domain. (A) Superposition of the complexes Na_V1.5 CT:Ca²⁺/CaM (PDB ID code 6MUD, this study) and Na_V1.4 IQ domain:Ca²⁺/CaM (PDB ID code 6MUE, this study). N-lobe and C-lobe are shown in green and blue, respectively, with light colors for the Na_V1.5 complex and dark colors for the Na_V1.4 complex. Na_V1.5 EF-hand domain (beige), Na_V1.5 IQ domain (red), and Na_V1.4 IQ domain (gray) are shown. Calcium ions are shown as white spheres. (B) Same superposition as in A but with the view from the N terminus of the IQ domain toward the C terminus. The EF-hand domain has been omitted and only the C-lobes are shown. This indicates a ∼90° rotation of the C-lobe binding to Na_V1.4 compared with the Na_V1.5 IQ domain. The Ile and Gln residues of the “IQ” motif are shown in black for reference. (C) Same superposition as in A, but only showing the Na_V1.5 CT (EF-hand domain in beige; IQ domain in red) and the C-lobe from the Na_V1.4 complex. This shows that the C-lobe would clash with the EF-hand domain, suggesting that, for it to bind in this mode, the EF-hand domain in Na_V1.4 would have to be displaced. (D) Superposition, based on helix 6, for the Na_V1.5 CT: mixed-CaM complex with FGF12B (PDB ID code 4JQ0) and for the Na_V1.4 IQ: Ca²⁺/CaM complex (PDB ID code 6MUE, this study). Shown are the Na_V1.5 CT (white) and FGF12B (yellow) from 4JQ0, and the C-lobe from the Na_V1.4 complex. This shows that, also in the presence of an FHF, there would be clashes between the Ca²⁺/C-lobe and the EF-hand domain. In addition, clashes would occur between Ca²⁺/Clobe and FGF12B.