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Cryo-EM structures of the human cation-chloride cotransporter KCC1

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Science  25 Oct 2019:
Vol. 366, Issue 6464, pp. 505-508
DOI: 10.1126/science.aay3129

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Coupled transport

Cation-chloride cotransporters move chloride and cations across the cell membrane and are important in regulating cell volume and setting the chloride concentration inside the cell. Mutations lead to serious diseases, such as epilepsy. Liu et al. present the structure of the human potassium-chloride cotransporter KCC1, as determined by cryo–electron microscopy. Based on the structure, functional studies, and molecular dynamics simulations, they propose an ion transport model. The structure provides a framework for interpreting disease-related mutations in potassium-chloride cotransporters.

Science, this issue p. 505

Abstract

Cation-chloride cotransporters (CCCs) mediate the coupled, electroneutral symport of cations with chloride across the plasma membrane and are vital for cell volume regulation, salt reabsorption in the kidney, and γ-aminobutyric acid (GABA)–mediated modulation in neurons. Here we present cryo–electron microscopy (cryo-EM) structures of human potassium-chloride cotransporter KCC1 in potassium chloride or sodium chloride at 2.9- to 3.5-angstrom resolution. KCC1 exists as a dimer, with both extracellular and transmembrane domains involved in dimerization. The structural and functional analyses, along with computational studies, reveal one potassium site and two chloride sites in KCC1, which are all required for the ion transport activity. KCC1 adopts an inward-facing conformation, with the extracellular gate occluded. The KCC1 structures allow us to model a potential ion transport mechanism in KCCs and provide a blueprint for drug design.

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