The Molecular Tweezer CLR01 Stabilizes a Disordered Protein-Protein Interface

Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition moti...

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Vydané v:	Journal of the American Chemical Society Ročník 139; číslo 45; s. 16256
Hlavní autori:	Bier, David, Mittal, Sumit, Bravo-Rodriguez, Kenny, Sowislok, Andrea, Guillory, Xavier, Briels, Jeroen, Heid, Christian, Bartel, Maria, Wettig, Burkhard, Brunsveld, Luc, Sanchez-Garcia, Elsa, Schrader, Thomas, Ottmann, Christian
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 15.11.2017
Predmet:	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism Amino Acid Motifs Binding Sites cdc25 Phosphatases - chemistry cdc25 Phosphatases - metabolism Entropy Intrinsically Disordered Proteins - chemistry Intrinsically Disordered Proteins - metabolism Ligands Models, Molecular Peptides - chemistry Peptides - metabolism Protein Binding Protein Conformation Protein Stability
ISSN:	1520-5126, 1520-5126
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Abstract	Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein-protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular "Janus" ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein-protein interface, "freezes" one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein.
AbstractList	Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein-protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular "Janus" ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein-protein interface, "freezes" one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein.Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein-protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular "Janus" ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein-protein interface, "freezes" one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein. Protein regions that are involved in protein-protein interactions (PPIs) very often display a high degree of intrinsic disorder, which is reduced during the recognition process. A prime example is binding of the rigid 14-3-3 adapter proteins to their numerous partner proteins, whose recognition motifs undergo an extensive disorder-to-order transition. In this context, it is highly desirable to control this entropy-costly process using tailored stabilizing agents. This study reveals how the molecular tweezer CLR01 tunes the 14-3-3/Cdc25CpS216 protein-protein interaction. Protein crystallography, biophysical affinity determination and biomolecular simulations unanimously deliver a remarkable finding: a supramolecular "Janus" ligand can bind simultaneously to a flexible peptidic PPI recognition motif and to a well-structured adapter protein. This binding fills a gap in the protein-protein interface, "freezes" one of the conformational states of the intrinsically disordered Cdc25C protein partner and enhances the apparent affinity of the interaction. This is the first structural and functional proof of a supramolecular ligand targeting a PPI interface and stabilizing the binding of an intrinsically disordered recognition motif to a rigid partner protein.
Author	Sanchez-Garcia, Elsa Wettig, Burkhard Bravo-Rodriguez, Kenny Brunsveld, Luc Ottmann, Christian Mittal, Sumit Sowislok, Andrea Guillory, Xavier Schrader, Thomas Briels, Jeroen Bartel, Maria Bier, David Heid, Christian
Author_xml	– sequence: 1 givenname: David surname: Bier fullname: Bier, David organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 2 givenname: Sumit surname: Mittal fullname: Mittal, Sumit organization: Max-Planck-Institut für Kohlenforschung , Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany – sequence: 3 givenname: Kenny surname: Bravo-Rodriguez fullname: Bravo-Rodriguez, Kenny organization: Max-Planck-Institut für Kohlenforschung , Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany – sequence: 4 givenname: Andrea surname: Sowislok fullname: Sowislok, Andrea organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 5 givenname: Xavier surname: Guillory fullname: Guillory, Xavier organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 6 givenname: Jeroen surname: Briels fullname: Briels, Jeroen organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 7 givenname: Christian surname: Heid fullname: Heid, Christian organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 8 givenname: Maria surname: Bartel fullname: Bartel, Maria organization: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands – sequence: 9 givenname: Burkhard surname: Wettig fullname: Wettig, Burkhard organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 10 givenname: Luc orcidid: 0000-0001-5675-511X surname: Brunsveld fullname: Brunsveld, Luc organization: Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology , Den Dolech 2, 5612 AZ Eindhoven, The Netherlands – sequence: 11 givenname: Elsa orcidid: 0000-0002-9211-5803 surname: Sanchez-Garcia fullname: Sanchez-Garcia, Elsa organization: Max-Planck-Institut für Kohlenforschung , Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany – sequence: 12 givenname: Thomas orcidid: 0000-0002-7003-6362 surname: Schrader fullname: Schrader, Thomas organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany – sequence: 13 givenname: Christian orcidid: 0000-0001-7315-0315 surname: Ottmann fullname: Ottmann, Christian organization: Department of Chemistry, University of Duisburg-Essen , Universitätsstrasse 7, 45117 Essen, Germany
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SubjectTerms	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism Amino Acid Motifs Binding Sites cdc25 Phosphatases - chemistry cdc25 Phosphatases - metabolism Entropy Intrinsically Disordered Proteins - chemistry Intrinsically Disordered Proteins - metabolism Ligands Models, Molecular Peptides - chemistry Peptides - metabolism Protein Binding Protein Conformation Protein Stability
Title	The Molecular Tweezer CLR01 Stabilizes a Disordered Protein-Protein Interface
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