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Molecular principles of assembly, activation, and inhibition in epithelial sodium channel.


ABSTRACT: The molecular bases of heteromeric assembly and link between Na+ self-inhibition and protease-sensitivity in epithelial sodium channels (ENaCs) are not fully understood. Previously, we demonstrated that ENaC subunits - ?, ?, and ? - assemble in a counterclockwise configuration when viewed from outside the cell with the protease-sensitive GRIP domains in the periphery (Noreng et al., 2018). Here we describe the structure of ENaC resolved by cryo-electron microscopy at 3 Å. We find that a combination of precise domain arrangement and complementary hydrogen bonding network defines the subunit arrangement. Furthermore, we determined that the ? subunit has a primary functional module consisting of the finger and GRIP domains. The module is bifurcated by the ?2 helix dividing two distinct regulatory sites: Na+ and the inhibitory peptide. Removal of the inhibitory peptide perturbs the Na+ site via the ?2 helix highlighting the critical role of the ?2 helix in regulating ENaC function.

SUBMITTER: Noreng S 

PROVIDER: S-EPMC7413742 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Molecular principles of assembly, activation, and inhibition in epithelial sodium channel.

Noreng Sigrid S   Posert Richard R   Bharadwaj Arpita A   Houser Alexandra A   Baconguis Isabelle I  

eLife 20200730


The molecular bases of heteromeric assembly and link between Na<sup>+</sup> self-inhibition and protease-sensitivity in epithelial sodium channels (ENaCs) are not fully understood. Previously, we demonstrated that ENaC subunits - α, β, and γ - assemble in a counterclockwise configuration when viewed from outside the cell with the protease-sensitive GRIP domains in the periphery (Noreng et al., 2018). Here we describe the structure of ENaC resolved by cryo-electron microscopy at 3 Å. We find that  ...[more]

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