Structural analyses of Ca2+/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation

Chaojian Wang, Ben C. Chung, Haidun Yan, Hong-Gang Wang, Seok-Yong Lee () and Geoffrey S. Pitt ()
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Chaojian Wang: Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
Ben C. Chung: Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
Haidun Yan: Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
Hong-Gang Wang: Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
Seok-Yong Lee: Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
Geoffrey S. Pitt: Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Ca2+ regulates voltage-gated Na+ (NaV) channels, and perturbed Ca2+ regulation of NaV function is associated with epilepsy syndromes, autism and cardiac arrhythmias. Understanding the disease mechanisms, however, has been hindered by a lack of structural information and competing models for how Ca2+ affects NaV channel function. Here we report the crystal structures of two ternary complexes of a human NaV cytosolic C-terminal domain (CTD), a fibroblast growth factor homologous factor and Ca2+/calmodulin (Ca2+/CaM). These structures rule out direct binding of Ca2+ to the NaV CTD and uncover new contacts between CaM and the NaV CTD. Probing these new contacts with biochemical and functional experiments allows us to propose a mechanism by which Ca2+ could regulate NaV channels. Further, our model provides hints towards understanding the molecular basis of the neurologic disorders and cardiac arrhythmias caused by NaV channel mutations.

Date: 2014
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DOI: 10.1038/ncomms5896

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