| Structural highlights
7tj8 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 3.2Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
SCN7A_HUMAN Sodium leak channel functioning as an osmosensor regulating sodium ion levels in various tissues and organs. While most sodium channels are voltage-gated, SCN7A is not and lets sodium flow through membrane along its concentration gradient (PubMed:26537257, PubMed:35301303). In glial cells of the central nervous system, senses body-fluid sodium levels and controls salt intake behavior as well as voluntary water intake through activation of nearby neurons to maintain appropriate sodium levels in the body (By similarity). By mediating sodium influx into keratinocytes, also plays a role in skin barrier homeostasis (PubMed:26537257).[UniProtKB:B1AYL1][1] [2]
Publication Abstract from PubMed
Unlike classical voltage-gated sodium (Na(V)) channels, Na(X) has been characterized as a voltage-insensitive, tetrodotoxin-resistant, sodium (Na(+))-activated channel involved in regulating Na(+) homeostasis. However, Na(X) remains refractory to functional characterization in traditional heterologous systems. Here, to gain insight into its atypical physiology, we determine structures of the human Na(X) channel in complex with the auxiliary beta3-subunit. Na(X) reveals structural alterations within the selectivity filter, voltage sensor-like domains, and pore module. We do not identify an extracellular Na(+)-sensor or any evidence for a Na(+)-based activation mechanism in Na(X). Instead, the S6-gate remains closed, membrane lipids fill the central cavity, and the domain III-IV linker restricts S6-dilation. We use protein engineering to identify three pore-wetting mutations targeting the hydrophobic S6-gate that unlock a robust voltage-insensitive leak conductance. This constitutively active Na(X)-QTT channel construct is non-selective among monovalent cations, inhibited by extracellular calcium, and sensitive to classical Na(V) channel blockers, including tetrodotoxin. Our findings highlight a functional diversity across the Na(V) channel scaffold, reshape our understanding of Na(X) physiology, and provide a template to demystify recalcitrant ion channels.
, PMID:35301303[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xu W, Hong SJ, Zhong A, Xie P, Jia S, Xie Z, Zeitchek M, Niknam-Bienia S, Zhao J, Porterfield DM, Surmeier DJ, Leung KP, Galiano RD, Mustoe TA. Sodium channel Nax is a regulator in epithelial sodium homeostasis. Sci Transl Med. 2015 Nov 4;7(312):312ra177. PMID:26537257 doi:10.1126/scitranslmed.aad0286
- ↑ Noland CL, Chua HC, Kschonsak M, Heusser SA, Braun N, Chang T, Tam C, Tang J, Arthur CP, Ciferri C, Pless SA, Payandeh J. Structure-guided unlocking of Na(X) reveals a non-selective tetrodotoxin-sensitive cation channel. Nat Commun. 2022 Mar 17;13(1):1416. PMID:35301303 doi:10.1038/s41467-022-28984-4
- ↑ Noland CL, Chua HC, Kschonsak M, Heusser SA, Braun N, Chang T, Tam C, Tang J, Arthur CP, Ciferri C, Pless SA, Payandeh J. Structure-guided unlocking of Na(X) reveals a non-selective tetrodotoxin-sensitive cation channel. Nat Commun. 2022 Mar 17;13(1):1416. PMID:35301303 doi:10.1038/s41467-022-28984-4
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