Binary architecture of the Na(v)1.2-β2 signaling complex

To investigate the mechanisms by which β-subunits influence Na(v) channel function, we solved the crystal structure of the β2 extracellular domain at 1.35Å. We combined these data with known bacterial Na(v) channel structural insights and novel functional studies to determine the interactions of specific residues in β2 with Na(v)1.2. We identified a flexible loop formed by (72)Cys and (75)Cys, a unique feature among the four β-subunit isoforms. Moreover, we found that (55)Cys helps to determine the influence of β2 on Na(v)1.2 toxin susceptibility. Further mutagenesis combined with the use of spider toxins reveals that (55)Cys forms a disulfide bond with (910)Cys in the Na(v)1.2 domain II pore loop, thereby suggesting a 1:1 stoichiometry. Our results also provide clues as to which disulfide bonds are formed between adjacent Na(v)1.2 (912/918)Cys residues. The concepts emerging from this work will help to form a model reflecting the β-subunit location in a Na(v) channel complex. DOI: http://dx.doi.org/10.7554/eLife.10960.001