title: Structural analyses of Ca²⁺/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation.
abstract: Ca(2+) regulates voltage-gated Na(+) (NaV) channels, and perturbed Ca(2+) 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 Ca(2+) 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 Ca(2+)/calmodulin (Ca(2+)/CaM). These structures rule out direct binding of Ca(2+) 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 Ca(2+) 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.
authors.affiliation: 1] Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [2] Division of Cardiology, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.affiliation: 1] Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [2] Department of Biochemistry, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.
authors.forename: Ben C
authors.initials: BC
authors.lastname: Chung
authors.affiliation: 1] Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [2] Division of Cardiology, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.
authors.forename: Haidun
authors.initials: H
authors.lastname: Yan
authors.affiliation: 1] Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [2] Division of Cardiology, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: 1] Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [2] Department of Biochemistry, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: 1] Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [2] Division of Cardiology, Department of Medicine, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA [3] Department of Pharmacology, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000737:chemistry*; D002147:Calmodulin / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000737:chemistry; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid
chemical_list: D002147:Calmodulin; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011994:Recombinant Proteins; C568320:SCN5A protein, human; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; D002118:Calcium