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Alignment of human Kv4 subfamily members Kv4.1, Kv4.2, and Kv4.3s (short isoform). Kv4.1 amino acid residues affected by the reported KCND1 variants are shown in color, and respective changes are indicated above using single-letter code (red: initially studied KCND1 group 1 variants; purple: additional maternally inherited missense variants, group 2). Regions highlighted in gray indicate the tetramerization (T1) domain and transmembrane segments S1S6, as indicated below. Sequence motifs critical for channel assembly trafficking and function are indicated by bold letters (HX5CX20CC motif in the T1-domain: Zn2+ coordination site;6 positively charged residues in S4: voltage sensor;7 potassium channel signature sequence GYGD in the pore loop [P]: selectivity filter;5 critical dynamic coupling residues, glutamate [E] in the S4-S5 linker, and proline-valine [PV] in the distal S6 segment: operation of the cytoplasmic gate;8,9,10,11 C-terminal di-leucine motif: dendritic targeting12). Numbers on the right specify amino acid residue positions. Sequences were aligned using Clustal Omega software (http://www.clustal.org/omega/). Residues that are perfectly conserved (*) or exhibit either strong or weak similarity (: or . for a scoring of >0.5 or <=0.5, respectively, in the Gonnet PAM 250 matrix) are indicated. Note that Kv4.1 amino acid residues in positions 57, 60, 61, 92, 99, 107, 115, 146, 308, 431, 450, 536, and 578 are fully conserved in all three Kv4 subfamily members.

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