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Nature. 2019 Aug;572(7770):488-492. doi: 10.1038/s41586-019-1438-2. Epub 2019 Jul 31.

Structure and mechanism of the cation-chloride cotransporter NKCC1.

Chew TA1,2, Orlando BJ3, Zhang J1, Latorraca NR1,2,4,5,6, Wang A1,4,5,6,7, Hollingsworth SA1,4,5,6,8, Chen DH6, Dror RO1,2,4,5,6, Liao M9, Feng L10,11,12.

Author information

1
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
2
Biophysics Program, Stanford University, Stanford, CA, USA.
3
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
4
Department of Computer Science, Stanford University, Stanford, CA, USA.
5
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
6
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
8
Merck & Co., South San Francisco, CA, USA.
9
Department of Cell Biology, Harvard Medical School, Boston, MA, USA. maofu_liao@hms.harvard.edu.
10
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. liangf@stanford.edu.
11
Biophysics Program, Stanford University, Stanford, CA, USA. liangf@stanford.edu.
12
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. liangf@stanford.edu.

Abstract

Cation-chloride cotransporters (CCCs) mediate the electroneutral transport of chloride, potassium and/or sodium across the membrane. They have critical roles in regulating cell volume, controlling ion absorption and secretion across epithelia, and maintaining intracellular chloride homeostasis. These transporters are primary targets for some of the most commonly prescribed drugs. Here we determined the cryo-electron microscopy structure of the Na-K-Cl cotransporter NKCC1, an extensively studied member of the CCC family, from Danio rerio. The structure defines the architecture of this protein family and reveals how cytosolic and transmembrane domains are strategically positioned for communication. Structural analyses, functional characterizations and computational studies reveal the ion-translocation pathway, ion-binding sites and key residues for transport activity. These results provide insights into ion selectivity, coupling and translocation, and establish a framework for understanding the physiological functions of CCCs and interpreting disease-related mutations.

PMID:
31367042
DOI:
10.1038/s41586-019-1438-2

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