Structure and mechanism of the cation-chloride cotransporter NKCC1

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. Thes...

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Bibliographic Details
Published in:Nature (London) 2019-08, Vol.572 (7770), p.488-492
Main Authors: Chew, Thomas A, Orlando, Benjamin J, Zhang, Jinru, Latorraca, Naomi R, Wang, Amy, Hollingsworth, Scott A, Chen, Dong-Hua, Dror, Ron O, Liao, Maofu, Feng, Liang
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Analysis
Animals
Automation
Binding Sites
Carrier proteins
Cations
Cations, Monovalent - metabolism
Cell size
Chloride
Chloride transport
Chlorides
Chlorides - metabolism
Computer applications
Cryoelectron Microscopy
Cytosol - metabolism
Domains
Electron microscopy
Gitelman Syndrome - genetics
Homeostasis
Humans
Hypertension
Ion Transport
Ion-permeable membranes
Lipids
Microscopy
Models, Molecular
Molecular Dynamics Simulation
Mutation
Physiology
Potassium
Potassium - metabolism
Potassium-chloride cotransporter
Protein Domains
Proteins
Secretion
Selectivity
Sodium
Sodium - metabolism
Solute Carrier Family 12, Member 2 - chemistry
Solute Carrier Family 12, Member 2 - genetics
Solute Carrier Family 12, Member 2 - metabolism
Solute Carrier Family 12, Member 2 - ultrastructure
Structure
Structure-function relationships
Translocation
Transmembrane domains
Transport
Zebra fish
Zebrafish - genetics
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Summary: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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-019-1438-2