ArticleThe Journal of biological chemistry2015
Functional Architecture of the Cytoplasmic Entrance to the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- Novel gain-of-function mutants identify a critical region within CFTR membrane-spanning domain 2 controlling cAMP-dependent and ATP-independent channel activation.Cellular and molecular life sciences : CMLS · 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
- Acting on the CFTR Membrane-Spanning Domains Interface Rescues Some Misfolded Mutants.International journal of molecular sciences · 2022Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- The molecular evolution of function in the CFTR chloride channel.The Journal of general physiology · 2021Article
- Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond.eLife · 2021Article
- Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator.iScience · 2021Article
- Two positively charged amino acid side-chains in the inner vestibule of the CFTR channel pore play analogous roles in controlling anion binding and anion conductance.Cellular and molecular life sciences : CMLS · 2021Article
- Life with Bacterial Mechanosensitive Channels, from Discovery to Physiology to Pharmacological Target.Microbiology and molecular biology reviews : MMBR · 2020Review
- Discovering the chloride pathway in the CFTR channel.Cellular and molecular life sciences : CMLS · 2020Article
- Functional and Pharmacological Characterization of the Rare CFTR Mutation W361R.Frontiers in pharmacology · 2020Article
- Contribution of the eighth transmembrane segment to the function of the CFTR chloride channel pore.Cellular and molecular life sciences : CMLS · 2019Article
- Combining theoretical and experimental data to decipher CFTR 3D structures and functions.Cellular and molecular life sciences : CMLS · 2018Article
- Functional organization of cytoplasmic portals controlling access to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel pore.The Journal of biological chemistry · 2018Article
- Structural mechanisms of CFTR function and dysfunction.The Journal of general physiology · 2018Review
- Functional characterization reveals that zebrafish CFTR prefers to occupy closed channel conformations.PloS one · 2018Article
- Cystic fibrosis transmembrane conductance regulator (CFTR): Making an ion channel out of an active transporter structure.Channels (Austin, Tex.) · 2018Review
- Architecture and functional properties of the CFTR channel pore.Cellular and molecular life sciences : CMLS · 2017Review
- Molecular modelling and molecular dynamics of CFTR.Cellular and molecular life sciences : CMLS · 2017Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
As an ion channel, the cystic fibrosis transmembrane conductance regulator must form a continuous pathway for the movement of Cl(-) and other anions between the cytoplasm and the extracellular solution. Both the structure and the function of the membrane-spanning part of this pathway are well defined. In contrast, the structure of the pathway that connects the cytoplasm to the membrane-spanning regions is unknown, and functional roles for different parts of the protein forming this pathway have not been described. We used patch clamp recording and substituted cysteine accessibility mutagenesis to identify positively charged amino acid side chains that attract cytoplasmic Cl(-) ions to the inner mouth of the pore. Our results indicate that the side chains of Lys-190, Arg-248, Arg-303, Lys-370, Lys-1041, and Arg-1048, located in different intracellular loops of the protein, play important roles in the electrostatic attraction of Cl(-) ions. Mutation and covalent modification of these residues have charge-dependent effects on the rate of Cl(-) permeation, demonstrating their functional role in maximization of Cl(-) flux. Other nearby positively charged side chains were not involved in electrostatic interactions with Cl(-). The location of these Cl(-)-attractive residues suggests that cytoplasmic Cl(-) ions enter the pore via a lateral portal located between the cytoplasmic extensions to the fourth and sixth transmembrane helices; a secondary, functionally less relevant portal might exist between the extensions to the 10th and 12th transmembrane helices. These results define the cytoplasmic mouth of the pore and show how it attracts Cl(-) ions from the cytoplasm.
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