PUBLICATION
Structure and mechanism of the cation-chloride cotransporter NKCC1
- Authors
- Chew, T.A., Orlando, B.J., Zhang, J., Latorraca, N.R., Wang, A., Hollingsworth, S.A., Chen, D.H., Dror, R.O., Liao, M., Feng, L.
- ID
- ZDB-PUB-190802-4
- Date
- 2019
- Source
- Nature 572(7770): 488-492 (Journal)
- Registered Authors
- Zhang, Jinru
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Binding Sites
- Cations, Monovalent/metabolism
- Chlorides/metabolism
- Cryoelectron Microscopy*
- Cytosol/metabolism
- Gitelman Syndrome/genetics
- Humans
- Ion Transport
- Models, Molecular
- Molecular Dynamics Simulation
- Potassium/metabolism
- Protein Domains
- 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*
- Zebrafish*/genetics
- PubMed
- 31367042 Full text @ Nature
Citation
Chew, T.A., Orlando, B.J., Zhang, J., Latorraca, N.R., Wang, A., Hollingsworth, S.A., Chen, D.H., Dror, R.O., Liao, M., Feng, L. (2019) Structure and mechanism of the cation-chloride cotransporter NKCC1. Nature. 572(7770):488-492.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping