Binary architecture of the Nav1.2-β2 signaling complex

Das, Samir; Gilchrist, John; Bosmans, Frank; Van Petegem, Filip

doi:10.7554/eLife.10960

Title: Binary architecture of the Na_v1.2-β2 signaling complex

Journal Article · Fri Feb 19 00:00:00 EST 2016 · eLife

DOI:https://doi.org/10.7554/eLife.10960· OSTI ID:1242297

Das, Samir ^[1]; Gilchrist, John ^[2]; Bosmans, Frank ^[2]; Van Petegem, Filip ^[1]

Univ. of British Columbia, Vancouver (Canada)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)

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_v1.2. We identified a flexible loop formed by ⁷²Cys and ⁷⁵Cys, a unique feature among the four β-subunit isoforms. Moreover, we found that ⁵⁵Cys helps to determine the influence of β2 on Na_v1.2 toxin susceptibility. Further mutagenesis combined with the use of spider toxins reveals that ⁵⁵Cys forms a disulfide bond with ⁹¹⁰Cys in the Na_v1.2 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_v1.2 ^912/918Cys residues. The concepts emerging from this work will help to form a model reflecting the β-subunit location in a Na_v channel complex.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; Canadian Inst. of Health Research; Human Frontier Science Program; Heart and Stroke Foundation of Canada

Grant/Contract Number:: 1R01NS091352; MOP-119404; RGY0064/2013; F31NS084646

OSTI ID:: 1242297

Journal Information:: eLife, Vol. 5; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 31 works

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Title: Binary architecture of the Na_v1.2-β2 signaling complex