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Crystallographic insights into sodium-channel modulation by the ?4 subunit.


ABSTRACT: Voltage-gated sodium (Nav) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, ?-subunits modify Nav channel function and cause debilitating disorders when mutated. While investigating whether ?-subunits also influence ligand interactions, we found that ?4 dramatically alters toxin binding to Nav1.2. To explore these observations further, we solved the crystal structure of the extracellular ?4 domain and identified (58)Cys as an exposed residue that, when mutated, eliminates the influence of ?4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of ?4. Disrupting this bridge by introducing a ?1 mutation implicated in epilepsy repositions the (58)Cys-containing loop and disrupts ?4 modulation of Nav1.2. Overall, the principles emerging from this work (i) help explain tissue-dependent variations in Nav channel pharmacology; (ii) enable the mechanistic interpretation of ?-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant ?-subunit behavior.

SUBMITTER: Gilchrist J 

PROVIDER: S-EPMC3870679 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Crystallographic insights into sodium-channel modulation by the β4 subunit.

Gilchrist John J   Das Samir S   Van Petegem Filip F   Bosmans Frank F   Bosmans Frank F  

Proceedings of the National Academy of Sciences of the United States of America 20131202 51


Voltage-gated sodium (Nav) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, β-subunits modify Nav channel function and cause debilitating disorders when mutated. While investigating whether β-subunits also influence ligand interactions, we found that β4 dramatically alters toxin binding to Nav1.2. To explore these observations further, we solved the crystal structure of the extracellul  ...[more]

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