ArticleJournal of molecular biology2008
Computational studies reveal phosphorylation-dependent changes in the unstructured R domain of CFTR.
Article in Journal of molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 55 citations in OpenAlex.
- Cryo-EM reveals a phosphorylated R-domain envelops the NBD1 catalytic domain in an ABC transporter.Life science alliance · 2024Article
- Full Rescue of F508del-CFTR Processing and Function by CFTR Modulators Can Be Achieved by Removal of Two Regulatory Regions.International journal of molecular sciences · 2020Article
- Experimentally-driven protein structure modeling.Journal of proteomics · 2020Review
- Changes in the R-region interactions depend on phosphorylation and contribute to PKA and PKC regulation of the cystic fibrosis transmembrane conductance regulator chloride channel.FASEB bioAdvances · 2020Article
- Intrinsic protein disorder reduces small-scale gene duplicability.DNA research : an international journal for rapid publication of reports on genes and genomes · 2017Article
- Molecular modelling and molecular dynamics of CFTR.Cellular and molecular life sciences : CMLS · 2017Review
- Long-range coupling between the extracellular gates and the intracellular ATP binding domains of multidrug resistance protein pumps and cystic fibrosis transmembrane conductance regulator channels.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.The Journal of biological chemistry · 2016Article
- Intrinsic Disorder in Transmembrane Proteins: Roles in Signaling and Topology Prediction.PloS one · 2016Article
- Phosphorylation-dependent changes in nucleotide binding, conformation, and dynamics of the first nucleotide binding domain (NBD1) of the sulfonylurea receptor 2B (SUR2B).The Journal of biological chemistry · 2015Article
- Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
- Restoration of NBD1 thermal stability is necessary and sufficient to correct ∆F508 CFTR folding and assembly.Journal of molecular biology · 2015Article
- An electrostatic interaction at the tetrahelix bundle promotes phosphorylation-dependent cystic fibrosis transmembrane conductance regulator (CFTR) channel opening.The Journal of biological chemistry · 2014Article
- Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions.The FEBS journal · 2013Review
- A SAXS-based ensemble model of the native and phosphorylated regulatory domain of the CFTR.Cellular and molecular life sciences : CMLS · 2013Article
- Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability.Cold Spring Harbor perspectives in medicine · 2013Review
- The CFTR ion channel: gating, regulation, and anion permeation.Cold Spring Harbor perspectives in medicine · 2013Article
- CFTR-SLC26 transporter interactions in epithelia.Biophysical reviews · 2012Article
- Functional Rescue of F508del-CFTR Using Small Molecule Correctors.Frontiers in pharmacology · 2012Article
- Structural models of CFTR-AMPK and CFTR-PKA interactions: R-domain flexibility is a key factor in CFTR regulation.Journal of molecular modeling · 2012Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent chloride channel that is mutated in cystic fibrosis, an inherited disease of high morbidity and mortality. The phosphorylation of its approximately 200 amino acid R domain by protein kinase A is obligatory for channel gating under normal conditions. The R domain contains more than ten PKA phosphorylation sites. No individual site is essential but phosphorylation of increasing numbers of sites enables progressively greater channel activity. In spite of numerous studies of the role of the R domain in CFTR regulation, its mechanism of action remains largely unknown. This is because neither its structure nor its interactions with other parts of CFTR have been completely elucidated. Studies have shown that the R domain lacks well-defined secondary structural elements and is an intrinsically disordered region of the channel protein. Here, we have analyzed the disorder pattern and employed computational methods to explore low-energy conformations of the R domain. The specific disorder and secondary structure patterns detected suggest the presence of molecular recognition elements (MoREs) that may mediate phosphorylation-regulated intra- and inter-domain interactions. Simulations were performed to generate an ensemble of accessible R domain conformations. Although the calculated structures may represent more compact conformers than occur in vivo, their secondary structure propensities are consistent with predictions and published experimental data. Equilibrium simulations of a mimic of a phosphorylated R domain showed that it exhibited an increased radius of gyration. In one possible interpretation of these findings, by changing its size, the globally unstructured R domain may act as an entropic spring to perturb the packing of membrane-spanning sequences that constitute the ion permeability pathway and thereby activate channel gating.
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