Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/8/1204 |
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| author | Jaka Kragelj Thibault Orand Elise Delaforge Laura Tengo Martin Blackledge Andrés Palencia Malene Ringkjøbing Jensen |
| author_facet | Jaka Kragelj Thibault Orand Elise Delaforge Laura Tengo Martin Blackledge Andrés Palencia Malene Ringkjøbing Jensen |
| author_sort | Jaka Kragelj |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T08:58:17Z |
| format | Article |
| id | doaj.art-3ab4ff216dac4200bd7a824cf22b4641 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T08:58:17Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-3ab4ff216dac4200bd7a824cf22b46412023-11-22T06:56:18ZengMDPI AGBiomolecules2218-273X2021-08-01118120410.3390/biom11081204Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein PartnersJaka Kragelj0Thibault Orand1Elise Delaforge2Laura Tengo3Martin Blackledge4Andrés Palencia5Malene Ringkjøbing Jensen6Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, FranceUniversité Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, FranceUniversité Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, FranceUniversité Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, FranceUniversité Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, FranceInstitute for Advanced Biosciences, Structural Biology of Novel Targets in Human Diseases, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, FranceUniversité Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, Grenoble, FranceIntrinsically 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.https://www.mdpi.com/2218-273X/11/8/1204NMR spectroscopyisothermal titration calorimetryintrinsically disordered protein (IDP)mitogen-activated protein kinase (MAPK)enthalpy–entropy compensationfolding-upon-binding |
| spellingShingle | Jaka Kragelj Thibault Orand Elise Delaforge Laura Tengo Martin Blackledge Andrés Palencia Malene Ringkjøbing Jensen Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners Biomolecules NMR spectroscopy isothermal titration calorimetry intrinsically disordered protein (IDP) mitogen-activated protein kinase (MAPK) enthalpy–entropy compensation folding-upon-binding |
| title | Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners |
| title_full | Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners |
| title_fullStr | Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners |
| title_full_unstemmed | Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners |
| title_short | Enthalpy–Entropy Compensation in the Promiscuous Interaction of an Intrinsically Disordered Protein with Homologous Protein Partners |
| title_sort | enthalpy entropy compensation in the promiscuous interaction of an intrinsically disordered protein with homologous protein partners |
| topic | NMR spectroscopy isothermal titration calorimetry intrinsically disordered protein (IDP) mitogen-activated protein kinase (MAPK) enthalpy–entropy compensation folding-upon-binding |
| url | https://www.mdpi.com/2218-273X/11/8/1204 |
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