4MZ3

Crystal structure of the voltage-gated sodium channel beta 4 subunit extracellular domain, C131W mutant

Summary for 4MZ3

• Entry DOI: 10.2210/pdb4mz3/pdb
• Related: 4MZ2
• Descriptor: Sodium channel subunit beta-4 (2 entities in total)
• Functional Keywords: ion conductance, extracellular, membrane protein
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein (Probable): Q8IWT1
• Total number of polymer chains: 2
• Total formula weight: 29529.16

Authors

Das, S.,Van Petegem, F. (deposition date: 2013-09-28, release date: 2013-12-04, Last modification date: 2024-11-20)

Primary citation

Gilchrist, J.,Das, S.,Van Petegem, F.,Bosmans, F.
Crystallographic insights into sodium-channel modulation by the beta 4 subunit.
Proc.Natl.Acad.Sci.USA, 110:E5016-E5024, 2013

PubMed 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, 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 extracellular β4 domain and identified (58)Cys 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 (58)Cys-containing loop and disrupts β4 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 β-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant β-subunit behavior.

PubMed: 24297919
DOI: 10.1073/pnas.1314557110

Experimental method

X-RAY DIFFRACTION (1.741 Å)