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

Author

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  • Chaojian Wang

    (Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court)

  • Ben C. Chung

    (Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court)

  • Haidun Yan

    (Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court)

  • Hong-Gang Wang

    (Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court)

  • Seok-Yong Lee

    (Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court)

  • Geoffrey S. Pitt

    (Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court
    Duke University Medical Center, 2 Genome Court)

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.

Suggested Citation

  • Chaojian Wang & Ben C. Chung & Haidun Yan & Hong-Gang Wang & Seok-Yong Lee & Geoffrey S. Pitt, 2014. "Structural analyses of Ca2+/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5896
    DOI: 10.1038/ncomms5896
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    Cited by:

    1. Annie M Westerlund & Lucie Delemotte, 2018. "Effect of Ca2+ on the promiscuous target-protein binding of calmodulin," PLOS Computational Biology, Public Library of Science, vol. 14(4), pages 1-27, April.

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