Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel β4 subunit explain its role in cell–cell adhesion
| Autor: | Takaho Terada, Fumitaka Oyama, Haruko Miyazaki, Shun-ichi Sekine, Shisako Shoji, Nobuyuki Nukina, Mikako Shirouzu, Hideaki Shimizu, Yoshiko Ishizuka-Katsura, Shigeyuki Yokoyama, Asako Tosaki, Noboru Ohsawa |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Recombinant Fusion Proteins Dimer CHO Cells Crystallography X-Ray Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound Cricetulus 0302 clinical medicine Cell Adhesion Extracellular Animals Humans membrane protein Protein Interaction Domains and Motifs Cysteine Cell adhesion Molecular Biology X-ray crystallography Voltage-Gated Sodium Channel beta-4 Subunit Chemistry Sodium channel Wild type Hydrogen Bonding Cell Biology Adhesion dimer Peptide Fragments Recombinant Proteins Transmembrane protein Cell biology immunoglobulin-like domain 030104 developmental biology Membrane protein Protein Structure and Folding Cystine Protein Conformation beta-Strand Navβ4 Protein Multimerization SCN4B Dimerization Hydrophobic and Hydrophilic Interactions 030217 neurology & neurosurgery sodium channel |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| Popis: | 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 α subunit and auxiliary β subunits, designated as β1/β1B–β4 (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 β4 subunit, which contributes to its adhesive function. Here, using crystallographic and biochemical analyses, we show that the β4 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 β4 mutant exhibited decreased cell adhesion compared with the wild type, indicating that the β4 cis dimer contributes to the trans homophilic interaction of β4 in cell–cell adhesion. Furthermore, this mutant exhibited increased association with the α subunit, indicating that the cis dimerization of β4 affects α–β4 complex formation. These observations provide the structural basis for the parallel dimer formation of β4 in VGSCs and reveal its mechanism in cell–cell adhesion. |
| Databáze: | OpenAIRE |
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