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

Publication Year
2021

Type

Journal Article
Abstract

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.

Journal
Proc Natl Acad Sci U S A
Volume
118
Issue
11
Date Published
2021 Mar 16
ISSN Number
1091-6490
Alternate Journal
Proc Natl Acad Sci U S A
PMCID
PMC7980448
PMID
33712547