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Crystallographic insights into sodium-channel modulation by the β4 subunit
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Crystallographic insights into sodium-channel modulation by the β4 subunit
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Journal Article
Crystallographic insights into sodium-channel modulation by the β4 subunit
2013
Overview
Voltage-gated sodium (Na ᵥ) 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 Na ᵥ 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 Na ᵥ1.2. To explore these observations further, we solved the crystal structure of the extracellular β4 domain and identified ⁵⁸Cys as an exposed residue that, when mutated, eliminates the influence of β4 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 β4. Disrupting this bridge by introducing a β1 mutation implicated in epilepsy repositions the ⁵⁸Cys-containing loop and disrupts β4 modulation of Na ᵥ1.2. Overall, the principles emerging from this work (i) help explain tissue-dependent variations in Na ᵥ channel pharmacology; (ii) enable the mechanistic interpretation of β-subunit–related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant β-subunit behavior.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ cysteine
/ epilepsy
/ Humans
/ mutation
/ NAV1.2 Voltage-Gated Sodium Channel - chemistry
/ NAV1.2 Voltage-Gated Sodium Channel - genetics
/ NAV1.2 Voltage-Gated Sodium Channel - metabolism
/ Protein Structure, Secondary
/ sodium
/ Structure-Activity Relationship
/ Voltage-Gated Sodium Channel beta-1 Subunit - chemistry
/ Voltage-Gated Sodium Channel beta-1 Subunit - genetics
/ Voltage-Gated Sodium Channel beta-1 Subunit - metabolism
/ Voltage-Gated Sodium Channel beta-4 Subunit - chemistry
/ Voltage-Gated Sodium Channel beta-4 Subunit - genetics
