ArticleProceedings of the National Academy of Sciences of the United States of America2008
Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 211 papers.
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Who cites it
211 citing papers in PubMed, 376 citations in OpenAlex.
- Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review.Current issues in molecular biology · 2025Review
- Selective amino acid formulation enhances anion secretion and restores function in cystic fibrosis mutations.Frontiers in pharmacology · 2025Article
- Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases.Israel journal of chemistry · 2024Article
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- In Silico and In Vitro Evaluation of the Mechanism of Action of Three VX809-Based Hybrid Derivatives as Correctors of the F508del CFTR Protein.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.Nature communications · 2023Article
- Elexacaftor Mediates the Rescue of F508del CFTR Functional Expression Interacting with MSD2.International journal of molecular sciences · 2023Article
- Review
- Tuning phenylalanine fluorination to assess aromatic contributions to protein function and stability in cells.Nature communications · 2023Article
- Recovery of ΔF508-CFTR Function by Citrate.Nutrients · 2022Article
- Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia.International journal of molecular sciences · 2022Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1.Computational and structural biotechnology journal · 2022Article
- The molecular evolution of function in the CFTR chloride channel.The Journal of general physiology · 2021Article
- Functional stability of CFTR depends on tight binding of ATP at its degenerate ATP-binding site.The Journal of physiology · 2021Article
- A topological switch in CFTR modulates channel activity and sensitivity to unfolding.Nature chemical biology · 2021Article
- DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy.Molecular biology of the cell · 2021Article
- Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation.Frontiers in physiology · 2021Review
- G551D mutation impairs PKA-dependent activation of CFTR channel that can be restored by novel GOF mutations.American journal of physiology. Lung cellular and molecular physiology · 2020Article
- Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2Biomolecules · 2020Review
151 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 4 institutions in 4 countries.
Funding
Abstract
Deletion of phenylalanine-508 (Phe-508) from the N-terminal nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ATP-binding cassette (ABC) transporter family, disrupts both its folding and function and causes most cystic fibrosis. Most mutant nascent chains do not pass quality control in the ER, and those that do remain thermally unstable, only partially functional, and are rapidly endocytosed and degraded. Although the lack of the Phe-508 peptide backbone diminishes the NBD1 folding yield, the absence of the aromatic side chain is primarily responsible for defective CFTR assembly and channel gating. However, the site of interdomain contact by the side chain is unknown as is the high-resolution 3D structure of the complete protein. Here we present a 3D structure of CFTR, constructed by molecular modeling and supported biochemically, in which Phe-508 mediates a tertiary interaction between the surface of NBD1 and a cytoplasmic loop (CL4) in the C-terminal membrane-spanning domain (MSD2). This crucial cytoplasmic membrane interface, which is dynamically involved in regulation of channel gating, explains the known sensitivity of CFTR assembly to many disease-associated mutations in CL4 as well as NBD1 and provides a sharply focused target for small molecules to treat CF. In addition to identifying a key intramolecular site to be repaired therapeutically, our findings advance understanding of CFTR structure and function and provide a platform for focused biochemical studies of other features of this unique ABC ion channel.
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