Structure of the CLC-1 chloride channel from Homo sapiens

Elife. 2018 May 29;7:e36629. doi: 10.7554/eLife.36629.

Abstract

CLC channels mediate passive Cl- conduction, while CLC transporters mediate active Cl- transport coupled to H+ transport in the opposite direction. The distinction between CLC-0/1/2 channels and CLC transporters seems undetectable by amino acid sequence. To understand why they are different functionally we determined the structure of the human CLC-1 channel. Its 'glutamate gate' residue, known to mediate proton transfer in CLC transporters, adopts a location in the structure that appears to preclude it from its transport function. Furthermore, smaller side chains produce a wider pore near the intracellular surface, potentially reducing a kinetic barrier for Cl- conduction. When the corresponding residues are mutated in a transporter, it is converted to a channel. Finally, Cl- at key sites in the pore appear to interact with reduced affinity compared to transporters. Thus, subtle differences in glutamate gate conformation, internal pore diameter and Cl- affinity distinguish CLC channels and transporters.

Keywords: CLC; chloride channel; cryoelectron microscopy; human; molecular biophysics; structural biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Chloride Channels / chemistry*
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Chlorides / metabolism*
  • Glutamic Acid / metabolism*
  • Humans
  • Ion Channel Gating*
  • Models, Molecular
  • Mutation
  • Protein Conformation

Substances

  • CLC-1 channel
  • Chloride Channels
  • Chlorides
  • Glutamic Acid