Evidence map›Paper›PMID 26888287›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2016

Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR.

Loes M Stevers, Chan V Lam, Seppe F R Leysen, Femke A Meijer, Daphne S van Scheppingen, Rens M J M de Vries, Graeme W Carlile, Lech G Milroy, David Y Thomas, Luc Brunsveld and 1 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.

0numbers the graph read from it
0cells of the map it votes in
71citing papers in PubMed
8.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

71 citing papers in PubMed, 135 citations in OpenAlex.

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  4. ProlineJournal of the American Chemical Society · 2025
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  17. Fragment-based exploration of the 14-3-3/Amot-p130 interface.Current research in structural biology · 2022
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11 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 3 institutions in 3 countries.

Loes M SteversLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Chan V LamLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Seppe F R LeysenLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Femke A MeijerLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Daphne S van ScheppingenLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Rens M J M de VriesLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Graeme W CarlileCystic Fibrosis Translational Research Centre, Department of Biochemistry, McGill University, Montreal, QC, Canada, H3G 1Y6;
Lech G MilroyLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
David Y ThomasCystic Fibrosis Translational Research Centre, Department of Biochemistry, McGill University, Montreal, QC, Canada, H3G 1Y6;
Luc BrunsveldLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands;
Christian OttmannLaboratory of Chemical Biology, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Institute for Complex Molecular Systems, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; Department of Chemistry, University of Duisburg-Essen, 45141 Essen, Germany c.ottmann@tue.nl.
Eindhoven University of Technology · NLMcGill University · CAUniversity of Duisburg-Essen · DE

Funding

Canadian Institutes of Health Research
6 · The paper itself

Abstract

Cystic fibrosis is a fatal genetic disease, most frequently caused by the retention of the CFTR (cystic fibrosis transmembrane conductance regulator) mutant protein in the endoplasmic reticulum (ER). The binding of the 14-3-3 protein to the CFTR regulatory (R) domain has been found to enhance CFTR trafficking to the plasma membrane. To define the mechanism of action of this protein-protein interaction, we have examined the interaction in vitro. The disordered multiphosphorylated R domain contains nine different 14-3-3 binding motifs. Furthermore, the 14-3-3 protein forms a dimer containing two amphipathic grooves that can potentially bind these phosphorylated motifs. This results in a number of possible binding mechanisms between these two proteins. Using multiple biochemical assays and crystal structures, we show that the interaction between them is governed by two binding sites: The key binding site of CFTR (pS768) occupies one groove of the 14-3-3 dimer, and a weaker, secondary binding site occupies the other binding groove. We show that fusicoccin-A, a natural-product tool compound used in studies of 14-3-3 biology, can stabilize the interaction between 14-3-3 and CFTR by selectively interacting with a secondary binding motif of CFTR (pS753). The stabilization of this interaction stimulates the trafficking of mutant CFTR to the plasma membrane. This definition of the druggability of the 14-3-3-CFTR interface might offer an approach for cystic fibrosis therapeutics.

Indexed as

14-3-3 ProteinsAmino Acid SequenceBinding SitesCalorimetryCystic Fibrosis Transmembrane Conductance RegulatorModels, MolecularMolecular Sequence Data14-3-3 ProteinsCystic Fibrosis Transmembrane Conductance Regulatordisordered proteinmultivalencyprotein–protein interaction

Identifiers

PMID26888287
PMCPMC4780605
OpenAlexW2285404847

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.