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

Sigrid Noreng, Richard Posert, Arpita Bharadwaj, Alexandra Houser, Isabelle Baconguis

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 – a, b, and g – 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 a subunit has a primary functional module consisting of the finger and GRIP domains. The module is bifurcated by the a2 helix dividing two distinct regulatory sites: Na+ and the inhibitory peptide. Removal of the inhibitory peptide perturbs the Na+ site via the a2 helix highlighting the critical role of the a2 helix in regulating ENaC function.

Original languageEnglish (US)
Article numbere59038
Pages (from-to)1-23
Number of pages23
JournaleLife
Volume9
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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