5xax | pdb_00005xax
Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel beta4 subunit explain its role in cell-cell adhesion
Structural highlights
Function[SCN4B_MOUSE] Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation. Modulates the suceptibility of the sodium channel to inhibition by toxic peptides from spider, scorpion, wasp and sea anemone venom (By similarity). Publication Abstract from PubMedVoltage-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 alpha subunit and auxiliary beta subunits, designated as beta1/beta1B-beta4 (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 beta4 subunit, which contributes to its adhesive function. Here, using crystallographic and biochemical analyses, we show that the beta4 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 beta4 mutant exhibited decreased cell adhesion compared with the wild type, indicating that the beta4 cis dimer contributes to the trans homophilic interaction of beta4 in cell-cell adhesion. Furthermore, this mutant exhibited increased association with the alpha subunit, indicating that the cis dimerization of beta4 affects alpha-beta4 complex formation. These observations provide the structural basis for the parallel dimer formation of beta4 in VGSCs and reveal its mechanism in cell-cell adhesion. Parallel homodimer structures of the extracellular domains of the voltage-gated sodium channel beta4 subunit explain its role in cell-cell adhesion.,Shimizu H, Tosaki A, Ohsawa N, Ishizuka-Katsura Y, Shoji S, Miyazaki H, Oyama F, Terada T, Shirouzu M, Sekine SI, Nukina N, Yokoyama S J Biol Chem. 2017 Aug 11;292(32):13428-13440. doi: 10.1074/jbc.M117.786509. Epub , 2017 Jun 27. PMID:28655765[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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