Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel 4 subunit explain its role in cell– cell adhesion

Hideaki Shimizu, Asako Tosaki, Noboru Ohsawa, Yoshiko Ishizuka-Katsura, Shisako Shoji, Haruko Miyazaki, Fumitaka Oyama, Takaho Terada, Mikako Shirouzu, Shun ichi Sekine, Nobuyuki Nukina, Shigeyuki Yokoyama

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Voltage-gated sodium channels (VGSCs) are transmembrane proteins required for the generation of action potentials in excitable cells and essential for propagating electrical impulses along nerve cells. VGSCs are complexes of a pore-forming subunit and auxiliary subunits, designated as 1/1B–4 (encoded by SCN1B– 4B, respectively), which also function in cell– cell adhesion. We previously reported the structural basis for the trans homophilic interaction of the 4 subunit, which contributes to its adhesive function. Here, using crystallographic and biochemical analyses, we show that the 4 extracellular domains directly interact with each other in a parallel manner that involves an intermolecular disulfide bond between the unpaired Cys residues (Cys58) in the loop connecting strands B and C and intermolecular hydrophobic and hydrogen-bonding interactions of the N-terminal segments (Ser30-Val35). Under reducing conditions, an N-terminally deleted 4 mutant exhibited decreased cell adhesion compared with the wild type, indicating that the 4 cis dimer contributes to the trans homophilic interaction of 4 in cell– cell adhesion. Furthermore, this mutant exhibited increased association with the subunit, indicating that the cis dimerization of 4 affects –4 complex formation. These observations provide the structural basis for the parallel dimer formation of 4 in VGSCs and reveal its mechanism in cell– cell adhesion.

Original languageEnglish
Pages (from-to)13428-13440
Number of pages13
JournalJournal of Biological Chemistry
Volume292
Issue number32
DOIs
Publication statusPublished - Aug 11 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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