Structure of the human epithelial sodium channel by cryo-electron microscopy

Elife. 2018 Sep 25;7:e39340. doi: 10.7554/eLife.39340.

Abstract

The epithelial sodium channel (ENaC), a member of the ENaC/DEG superfamily, regulates Na+ and water homeostasis. ENaCs assemble as heterotrimeric channels that harbor protease-sensitive domains critical for gating the channel. Here, we present the structure of human ENaC in the uncleaved state determined by single-particle cryo-electron microscopy. The ion channel is composed of a large extracellular domain and a narrow transmembrane domain. The structure reveals that ENaC assembles with a 1:1:1 stoichiometry of α:β:γ subunits arranged in a counter-clockwise manner. The shape of each subunit is reminiscent of a hand with key gating domains of a 'finger' and a 'thumb.' Wedged between these domains is the elusive protease-sensitive inhibitory domain poised to regulate conformational changes of the 'finger' and 'thumb'; thus, the structure provides the first view of the architecture of inhibition of ENaC.

Keywords: Cryo-EM; Ion Channel; electrophysiology; heterotrimer; human; molecular biophysics; structural biology; structure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Cryoelectron Microscopy*
  • Epithelial Sodium Channels / chemistry
  • Epithelial Sodium Channels / ultrastructure*
  • Homeostasis
  • Humans
  • Ion Channel Gating / genetics*
  • Ion Transport / genetics
  • Protein Domains / genetics
  • Protein Subunits / chemistry
  • Signal Transduction / genetics
  • Sodium / chemistry
  • Sodium / metabolism*
  • Water / chemistry
  • Water / metabolism

Substances

  • Epithelial Sodium Channels
  • Protein Subunits
  • Water
  • Sodium