ArticleProceedings of the National Academy of Sciences of the United States of America2015
Localizing a gate in CFTR.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- A cluster of inhibitory residues in the regulatory domain prevents activation of the cystic fibrosis transmembrane conductance regulator.The Journal of biological chemistry · 2025Article
- Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.Nature communications · 2024Article
- Structural identification of a selectivity filter in CFTR.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Molecular dynamics study of ClCellular and molecular life sciences : CMLS · 2023Article
- Whole-Exome Sequencing IdentifiedFrontiers in genetics · 2021Article
- Fluorescence assay for simultaneous quantification of CFTR ion-channel function and plasma membrane proximity.The Journal of biological chemistry · 2020Article
- Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas.FEBS letters · 2020Review
- Positional effects of premature termination codons on the biochemical and biophysical properties of CFTR.The Journal of physiology · 2020Article
- Identifying the molecular target sites for CFTR potentiators GLPG1837 and VX-770.The Journal of general physiology · 2019Article
- Contribution of the eighth transmembrane segment to the function of the CFTR chloride channel pore.Cellular and molecular life sciences : CMLS · 2019Article
- Structural mechanisms for defective CFTR gating caused by the Q1412X mutation, a severe Class VI pathogenic mutation in cystic fibrosis.The Journal of physiology · 2019Article
- Molecular structure of the ATP-bound, phosphorylated human CFTR.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Combining theoretical and experimental data to decipher CFTR 3D structures and functions.Cellular and molecular life sciences : CMLS · 2018Article
- Conformational change of the extracellular parts of the CFTR protein during channel gating.Cellular and molecular life sciences : CMLS · 2018Article
- Structure of Transmembrane Helix 8 and Possible Membrane Defects in CFTR.Biophysical journal · 2018Article
- Structural mechanisms of CFTR function and dysfunction.The Journal of general physiology · 2018Review
- Cystic fibrosis transmembrane conductance regulator (CFTR): Making an ion channel out of an active transporter structure.Channels (Austin, Tex.) · 2018Review
- Functional characterization reveals that zebrafish CFTR prefers to occupy closed channel conformations.PloS one · 2018Article
- Transmembrane helical interactions in the CFTR channel pore.PLoS computational biology · 2017Article
- Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation.The Journal of biological chemistry · 2017Article
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2 authors.
Funding
Abstract
Experimental and computational studies have painted a picture of the chloride permeation pathway in cystic fibrosis transmembrane conductance regulator (CFTR) as a short narrow tunnel flanked by wider inner and outer vestibules. Although these studies also identified a number of transmembrane segments (TMs) as pore-lining, the exact location of CFTR's gate(s) remains unknown. Here, using a channel-permeant probe, [Au(CN)2](-), we provide evidence that CFTR bears a gate that coincides with the predicted narrow section of the pore defined as residues 338-341 in TM6. Specifically, cysteines introduced cytoplasmic to the narrow region (i.e., positions 344 in TM6 and 1148 in TM12) can be modified by intracellular [Au(CN)2](-) in both open and closed states, corroborating the conclusion that the internal vestibule does not harbor a gate. However, cysteines engineered to positions external to the presumed narrow region (e.g., 334, 335, and 337 in TM6) are all nonreactive toward cytoplasmic [Au(CN)2](-) in the absence of ATP, whereas they can be better accessed by extracellular [Au(CN)2](-) when the open probability is markedly reduced by introducing a second mutation, G1349D. As [Au(CN)2](-) and chloride ions share the same permeation pathway, these results imply a gate is situated between amino acid residues 337 and 344 along TM6, encompassing the very segment that may also serve as the selectivity filter for CFTR. The unique position of a gate in the middle of the ion translocation pathway diverges from those seen in ATP-binding cassette (ABC) transporters and thus distinguishes CFTR from other members of the ABC transporter family.
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