Figure 7. Mutations affecting CTNa_v1.5-CaM and CTNa_v1.5-CTNa_v1.5 interactions.

(a) and (b). Electrophysiological features of Na⁺ channel variants altered at the CTNa_v1.5-CaM-Ca²⁺ interaction interface. Activation and steady state inactivation of wild type (circles) and mutant channels (squares). The data are fit to a Boltzman function as described in Methods. Mutant channels and Q1909R and K1922A exhibit a depolarizing shift in the V_0.5 of inactivation (Supplementary Fig. 5). (c) Surface representation of one monomer (orange) interacting with a neighboring molecule (lime green). CTNa_v1.5 with LQT3 mutations (1795,1825, 1840,1895,1909 and 1924) shown in grey and brugada syndrome mutations in blue (1837,1901,1904,1919). Epilepsy mutations at the interface with CaM-C-term lobe (1895 and 1852) are shown in purple; Brugada mutations (1901 and 1904) are at the interface of CTNa_v1.5 with the CaM-C-term lobe (blue) and 1705, 1825, 1840, 1924 are at the CTNa_v1.5-CTNa_v1.5 interface. Residues 1788, 1790, 1792, 1799, shown in dark red, line the EFL binding site for helix αVI residues past the IQ motif ¹⁴. Residues of the FGF13 that contact the EFL domain are colored turquoise. (d) Same as (c) displaying the neighboring CTNa_v1.5(e) Same orientation as in panels c and d including CaM as a magenta ribbon.