Structural analyses of Ca²⁺/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation.
Publication Type:Journal Article
Source:Nat Commun, Volume 5, p.4896 (2014)
Keywords:Amino Acid Sequence, Calcium, Calmodulin, Crystallography, X-Ray, Cytosol, Fibroblast Growth Factors, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, NAV1.2 Voltage-Gated Sodium Channel, NAV1.5 Voltage-Gated Sodium Channel, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins, Sequence Homology, Amino Acid
<p>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.</p>