Conformational changes required for H(+)/Cl(-) exchange mediated by a CLC transporter

Nat Struct Mol Biol. 2014 May;21(5):456-63. doi: 10.1038/nsmb.2814. Epub 2014 Apr 20.


CLC-type exchangers mediate transmembrane Cl(-) transport. Mutations altering their gating properties cause numerous genetic disorders. However, their transport mechanism remains poorly understood. In conventional models, two gates alternatively expose substrates to the intra- or extracellular solutions. A glutamate was identified as the only gate in the CLCs, suggesting that CLCs function by a nonconventional mechanism. Here we show that transport in CLC-ec1, a prokaryotic homolog, is inhibited by cross-links constraining movement of helix O far from the transport pathway. Cross-linked CLC-ec1 adopts a wild-type-like structure, indicating stabilization of a native conformation. Movements of helix O are transduced to the ion pathway via a direct contact between its C terminus and a tyrosine that is a constitutive element of the second gate of CLC transporters. Therefore, the CLC exchangers have two gates that are coupled through conformational rearrangements outside the ion pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport / physiology
  • Chloride Channels / chemistry*
  • Chloride Channels / genetics
  • Chloride Channels / physiology
  • Crystallography, X-Ray
  • Escherichia coli K12 / metabolism
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / physiology
  • Models, Molecular
  • Mutation
  • Protein Structure, Tertiary


  • Chloride Channels
  • Escherichia coli Proteins

Associated data

  • PDB/4MQX