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

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.

SUBMITTER: Shimizu H 

PROVIDER: S-EPMC5555201 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature