Journal
ELIFE
Volume 5, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.10960
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Funding
- National Institutes of Health [1R01NS091352, F31NS084646]
- Canadian Institutes of Health Research [MOP-119404]
- Human Frontier Science Program [RGY0064/2013]
- Heart and Stroke Foundation of Canada
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To investigate the mechanisms by which beta-subunits influence Nav channel function, we solved the crystal structure of the beta 2 extracellular domain at 1.35A. We combined these data with known bacterial Nav channel structural insights and novel functional studies to determine the interactions of specific residues in beta 2 with Nav1.2. We identified a flexible loop formed by (72)Cys and (75)Cys, a unique feature among the four beta-subunit isoforms. Moreover, we found that (55)Cys helps to determine the influence of beta 2 on Nav1.2 toxin susceptibility. Further mutagenesis combined with the use of spider toxins reveals that (55)Cys forms a disulfide bond with 91 Cys in the Nav1.2 domain II pore loop, thereby suggesting a 1:1 stoichiometry. Our results also provide clues as to which disulfide bonds are formed between adjacent Nav1.2 (CyS)-Cy-912/918 residues. The concepts emerging from this work will help to form a model reflecting the beta-subunit location in a Nav channel complex.
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