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

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 t...

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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS Jg. 113; H. 9; S. E1152
Hauptverfasser:	Stevers, Loes M, Lam, Chan V, Leysen, Seppe F R, Meijer, Femke A, van Scheppingen, Daphne S, de Vries, Rens M J M, Carlile, Graeme W, Milroy, Lech G, Thomas, David Y, Brunsveld, Luc, Ottmann, Christian
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 01.03.2016
Schlagworte:	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism Amino Acid Sequence Binding Sites Calorimetry Cystic Fibrosis Transmembrane Conductance Regulator - chemistry Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Models, Molecular Molecular Sequence Data protein–protein interaction multivalency disordered protein
ISSN:	1091-6490, 1091-6490
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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.
AbstractList	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.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. 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.
Author	Milroy, Lech G Carlile, Graeme W Lam, Chan V Brunsveld, Luc Leysen, Seppe F R Ottmann, Christian de Vries, Rens M J M Stevers, Loes M Meijer, Femke A Thomas, David Y van Scheppingen, Daphne S
Author_xml	– sequence: 1 givenname: Loes M surname: Stevers fullname: Stevers, Loes M organization: Laboratory 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 – sequence: 2 givenname: Chan V surname: Lam fullname: Lam, Chan V organization: Laboratory 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 – sequence: 3 givenname: Seppe F R surname: Leysen fullname: Leysen, Seppe F R organization: Laboratory 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 – sequence: 4 givenname: Femke A surname: Meijer fullname: Meijer, Femke A organization: Laboratory 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 – sequence: 5 givenname: Daphne S surname: van Scheppingen fullname: van Scheppingen, Daphne S organization: Laboratory 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 – sequence: 6 givenname: Rens M J M surname: de Vries fullname: de Vries, Rens M J M organization: Laboratory 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 – sequence: 7 givenname: Graeme W surname: Carlile fullname: Carlile, Graeme W organization: Cystic Fibrosis Translational Research Centre, Department of Biochemistry, McGill University, Montreal, QC, Canada, H3G 1Y6 – sequence: 8 givenname: Lech G surname: Milroy fullname: Milroy, Lech G organization: Laboratory 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 – sequence: 9 givenname: David Y surname: Thomas fullname: Thomas, David Y organization: Cystic Fibrosis Translational Research Centre, Department of Biochemistry, McGill University, Montreal, QC, Canada, H3G 1Y6 – sequence: 10 givenname: Luc surname: Brunsveld fullname: Brunsveld, Luc organization: Laboratory 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 – sequence: 11 givenname: Christian surname: Ottmann fullname: Ottmann, Christian email: c.ottmann@tue.nl organization: Laboratory 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
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Snippet	Cystic fibrosis is a fatal genetic disease, most frequently caused by the retention of the CFTR (cystic fibrosis transmembrane conductance regulator) mutant...
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SubjectTerms	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism Amino Acid Sequence Binding Sites Calorimetry Cystic Fibrosis Transmembrane Conductance Regulator - chemistry Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Models, Molecular Molecular Sequence Data
Title	Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR
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