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Insight into Calcium-Binding Motifs of Intrinsically Disordered Proteins
Article

Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners

1
Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, France
2
Institute for Advanced Biosciences, Structural Biology of Novel Targets in Human Diseases, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
§
Present address: European Molecular Biology Laboratory, Grenoble, France.
Academic Editors: Nathalie Sibille, Sonia Longhi and Carine Van Heijenoort
Biomolecules 2021, 11(8), 1204; https://doi.org/10.3390/biom11081204
Received: 13 July 2021 / Revised: 1 August 2021 / Accepted: 9 August 2021 / Published: 13 August 2021
Intrinsically disordered proteins (IDPs) can engage in promiscuous interactions with their protein targets; however, it is not clear how this feature is encoded in the primary sequence of the IDPs and to what extent the surface properties and the shape of the binding cavity dictate the binding mode and the final bound conformation. Here we show, using a combination of nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC), that the promiscuous interaction of the intrinsically disordered regulatory domain of the mitogen-activated protein kinase kinase MKK4 with p38α and JNK1 is facilitated by folding-upon-binding into two different conformations, despite the high sequence conservation and structural homology between p38α and JNK1. Our results support a model whereby the specific surface properties of JNK1 and p38α dictate the bound conformation of MKK4 and that enthalpy–entropy compensation plays a major role in maintaining comparable binding affinities for MKK4 towards the two kinases. View Full-Text
Keywords: NMR spectroscopy; isothermal titration calorimetry; intrinsically disordered protein (IDP); mitogen-activated protein kinase (MAPK); enthalpy–entropy compensation; folding-upon-binding; chemical exchange saturation transfer (CEST) NMR spectroscopy; isothermal titration calorimetry; intrinsically disordered protein (IDP); mitogen-activated protein kinase (MAPK); enthalpy–entropy compensation; folding-upon-binding; chemical exchange saturation transfer (CEST)
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MDPI and ACS Style

Kragelj, J.; Orand, T.; Delaforge, E.; Tengo, L.; Blackledge, M.; Palencia, A.; Jensen, M.R. Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners. Biomolecules 2021, 11, 1204. https://doi.org/10.3390/biom11081204

AMA Style

Kragelj J, Orand T, Delaforge E, Tengo L, Blackledge M, Palencia A, Jensen MR. Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners. Biomolecules. 2021; 11(8):1204. https://doi.org/10.3390/biom11081204

Chicago/Turabian Style

Kragelj, Jaka, Thibault Orand, Elise Delaforge, Laura Tengo, Martin Blackledge, Andrés Palencia, and Malene R. Jensen. 2021. "Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners" Biomolecules 11, no. 8: 1204. https://doi.org/10.3390/biom11081204

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