Comparative structural analysis of human Na1.1 and Na1.5 reveals mutational hotspots for sodium channelopathies.

TitleComparative structural analysis of human Na1.1 and Na1.5 reveals mutational hotspots for sodium channelopathies.
Publication TypeJournal Article
Year of Publication2021
AuthorsPan, X, Li, Z, Jin, X, Zhao, Y, Huang, G, Huang, X, Shen, Z, Cao, Y, Dong, M, Lei, J, Yan, N
JournalProc Natl Acad Sci U S A
Volume118
Issue11
Date Published2021 03 16
ISSN1091-6490
KeywordsChannelopathies, Cryoelectron Microscopy, Humans, Models, Molecular, Mutation, NAV1.1 Voltage-Gated Sodium Channel, NAV1.5 Voltage-Gated Sodium Channel, Protein Conformation, Protein Subunits, Structure-Activity Relationship
Abstract

<p>Among the nine subtypes of human voltage-gated sodium (Na) channels, the brain and cardiac isoforms, Na1.1 and Na1.5, each carry more than 400 missense mutations respectively associated with epilepsy and cardiac disorders. High-resolution structures are required for structure-function relationship dissection of the disease variants. We report the cryo-EM structures of the full-length human Na1.1-β4 complex at 3.3 Å resolution here and the Na1.5-E1784K variant in the accompanying paper. Up to 341 and 261 disease-related missense mutations in Na1.1 and Na1.5, respectively, are resolved. Comparative structural analysis reveals several clusters of disease mutations that are common to both Na1.1 and Na1.5. Among these, the majority of mutations on the extracellular loops above the pore domain and the supporting segments for the selectivity filter may impair structural integrity, while those on the pore domain and the voltage-sensing domains mostly interfere with electromechanical coupling and fast inactivation. Our systematic structural delineation of these mutations provides important insight into their pathogenic mechanism, which will facilitate the development of precise therapeutic interventions against various sodium channelopathies.</p>

DOI10.1073/pnas.2100066118
Alternate JournalProc Natl Acad Sci U S A
PubMed ID33712547
PubMed Central IDPMC7980448