Structure of a volume-regulated anion channel of the LRRC8 family

Nature. 2018 Jun;558(7709):254-259. doi: 10.1038/s41586-018-0134-y. Epub 2018 May 16.

Abstract

Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, we determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Our work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Connexins / chemistry
  • Cryoelectron Microscopy*
  • Crystallography, X-Ray
  • Cytoplasm / metabolism
  • HEK293 Cells
  • Humans
  • Ion Channel Gating*
  • Leucine-Rich Repeat Proteins
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Membrane Proteins / ultrastructure*
  • Mice
  • Models, Molecular
  • Protein Domains
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • Proteins / chemistry*
  • Proteins / metabolism
  • Proteins / ultrastructure*
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Connexins
  • LRRC8A protein, human
  • LRRC8A protein, mouse
  • Leucine-Rich Repeat Proteins
  • Membrane Proteins
  • Protein Subunits
  • Proteins