Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle.

Publication Type:

Journal Article


Science, Volume 330, Issue 6004, p.635-41 (2010)


Algal Proteins, Animals, Antiporters, Binding Sites, Cell Line, Cell Membrane, Chloride Channels, Chlorides, Crystallization, Crystallography, X-Ray, Cystathionine beta-Synthase, Cytoplasm, Glutamic Acid, Ion Channel Gating, Ion Transport, Models, Biological, Models, Molecular, Protein Conformation, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Subunits, Protons, Rhodophyta


<p>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.</p>