Research Article

Structure of a Eukaryotic CLC Transporter Defines an Intermediate State in the Transport Cycle

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Science  29 Oct 2010:
Vol. 330, Issue 6004, pp. 635-641
DOI: 10.1126/science.1195230

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Controlling Chloride Channels

The CLC proteins are a large family of channels and transporters that transfer chloride ions across cell membranes. While structures of two prokaryotic CLCs have been determined, these do not include the cytoplasmic regulatory domains found in eukaryotic transporters, and the structures do not reveal the mechanism of Cl/H+–coupled transport. L. Feng et al. (p. 635, published online 30 September; see the Perspective by Mindell) describe the structure of a eukaryotic CLC protein and found that the regulatory domains interacted closely with the transmembrane domain so that conformational changes are transmitted to the ion pathway. A gating glutamate in the eukaryote transporter is in a different conformation to prokaryotic structures, explaining the 2:1 stoichiometry of Cl/H+ exchange in eukaryotes.


CLC proteins transport chloride (Cl) ions across cell membranes to control the electrical potential of muscle cells, transfer electrolytes across epithelia, and control the pH and electrolyte composition of intracellular organelles. Some members of this protein family are Cl ion channels, whereas others are secondary active transporters that exchange Cl ions and protons (H+) with a 2:1 stoichiometry. We have determined the structure of a eukaryotic CLC transporter at 3.5 angstrom resolution. Cytoplasmic cystathionine beta-synthase (CBS) domains are strategically positioned to regulate the ion-transport pathway, and many disease-causing mutations in human CLCs reside on the CBS-transmembrane interface. Comparison with prokaryotic CLC shows that a gating glutamate residue changes conformation and suggests a basis for 2:1 Cl/H+ exchange and a simple mechanistic connection between CLC channels and transporters.

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