Fig. 3

Effect of amino acid exchanges on the SCN2A structure. a Top view on a model of the SCN2A structure. The four homologous repeats are shown in different colors (blue, cyan, orange, red) and the III-IV domain linker is shown in purple. The site of the pore is marked by a black diamond and the positions of the missense variants investigated in the present study are indicated. The extracellular sequence stretch spanning residues 275–359 has been omitted for clarity. b Side-view on the SCN2A structure. Color coding as in (a). c Model of the SCN2A pore region. The four residues that are critical for Na⁺ selectivity are shown in stick presentation. d In the wild-type SCN2A (left panel) the sidechain orientation of E942, which is part of the selectivity filter, is stabilized by polar interactions with R937 (see encircled region). These interactions cannot be formed in the R937C variant (right panel) by the shorter and uncharged cysteine sidechain thus impeding fixation of the E942 sidechain (flexibility is indicated by the magenta arrow). e E1803 forms interactions with residues Q1510 and P1512 of the III-IV domain linker, which cannot be formed in the (f) E1803G variant. The lacking interactions are highlighted by a blue dotted circle. g L1342 forms sidechain interactions with W864 of the adjacent repeat. h In the L1342P variant, these interactions cannot be formed by the less-extended proline sidechain. i L1563 forms hydrophobic interactions within the fourth domain. k These interactions are partially lost in the L1563V variant by the shorter valine sidechain (indicated by a blue dotted circle)