Research Articles

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

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Science  30 Sep 2010:
DOI: 10.1126/science.1195230


CLC proteins transport 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, while others are secondary active transporters that exchange Cl ions and H+ with a 2:1 stoichiometry. We have determined the structure of a eukaryotic CLC transporter at 3.5 Å resolution. Cytoplasmic 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 changes conformation and suggests a basis for 2:1 Cl/H+ exchange and a simple mechanistic connection between CLC channels and transporters.