6vsv | pdb_00006vsv
Crystal structure of a disease mutant of the Voltage-gated Sodium Channel Beta 4 subunit extracellular domain
Structural highlights
Disease[SCN4B_HUMAN] Romano-Ward syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function[SCN4B_HUMAN] Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation (By similarity). Publication Abstract from PubMedBackground: Voltage-gated sodium (NaV) channels help regulate electrical activity of the plasma membrane. Mutations in associated subunits can result in pathological outcomes. Here we examined the interaction of NaV channels with cardiac arrhythmia-linked mutations in SCN2B and SCN4B, two genes that encode auxiliary beta-subunits. Materials and Methods: To investigate changes in SCN2B (R137H) and SCN4B (I80T) function, we combined three-dimensional X-ray crystallography with electrophysiological measurements on NaV1.5, the dominant subtype in the heart. Results: SCN4B (I80T) alters channel activity, whereas SCN2B (R137H) does not have an apparent effect. Structurally, the SCN4B (I80T) perturbation alters hydrophobic packing of the subunit with major structural changes and causes a thermal destabilization of the folding. In contrast, SCN2B (R137H) leads to structural changes but overall protein stability is unaffected. Conclusion: SCN4B (I80T) data suggest a functionally important region in the interaction between NaV1.5 and beta4 that, when disrupted, could lead to channel dysfunction. A lack of apparent functional effects of SCN2B (R137H) on NaV1.5 suggests an alternative working mechanism, possibly through other NaV channel subtypes present in heart tissue. Indeed, mapping the structural variations of SCN2B (R137H) onto neuronal NaV channel structures suggests altered interaction patterns. Biophysical Investigation of Sodium Channel Interaction with beta-Subunit Variants Associated with Arrhythmias.,Llongueras JP, Das S, De Waele J, Capulzini L, Sorgente A, Van Petegem F, Bosmans F Bioelectricity. 2020 Sep 1;2(3):269-278. doi: 10.1089/bioe.2020.0030. Epub 2020, Sep 16. PMID:34476357[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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