Dynamics, Conformational Entropy, and Frustration in Protein–Protein Interactions Involving an Intrinsically Disordered Protein Domain
| العنوان: | Dynamics, Conformational Entropy, and Frustration in Protein–Protein Interactions Involving an Intrinsically Disordered Protein Domain |
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| المؤلفون: | Ida Lindström, Jakob Dogan |
| المصدر: | ACS Chemical Biology. 13:1218-1227 |
| بيانات النشر: | American Chemical Society (ACS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Entropy, Protein domain, Calorimetry, 010402 general chemistry, Intrinsically disordered proteins, 01 natural sciences, Biochemistry, Protein–protein interaction, Hydrophobic effect, 03 medical and health sciences, Protein Interaction Mapping, Protein Interaction Domains and Motifs, CREB-binding protein, biology, Chemistry, STAT2 Transcription Factor, Isothermal titration calorimetry, General Medicine, Conformational entropy, CREB-Binding Protein, 0104 chemical sciences, Intrinsically Disordered Proteins, Kinetics, 030104 developmental biology, biology.protein, Biophysics, Molecular Medicine, Hydrophobic and Hydrophilic Interactions, Protein Binding, Entropy (order and disorder) |
| الوصف: | Intrinsically disordered proteins (IDPs) are abundant in the eukaryotic proteome. However, little is known about the role of subnanosecond dynamics and the conformational entropy that it represents in protein-protein interactions involving IDPs. Using nuclear magnetic resonance side chain and backbone relaxation, stopped-flow kinetics, isothermal titration calorimetry, and computational studies, we have characterized the interaction between the globular TAZ1 domain of the CREB binding protein and the intrinsically disordered transactivation domain of STAT2 (TAD-STAT2). We show that the TAZ1/TAD-STAT2 complex retains considerable subnanosecond motions, with TAD-STAT2 undergoing only a partial disorder-to-order transition. We report here the first experimental determination of the conformational entropy change for both binding partners in an IDP binding interaction and find that the total change even exceeds in magnitude the binding enthalpy and is comparable to the contribution from the hydrophobic effect, demonstrating its importance in the binding energetics. Furthermore, we show that the conformational entropy change for TAZ1 is also instrumental in maintaining a biologically meaningful binding affinity. Strikingly, a spatial clustering of very high amplitude motions and a cluster of more rigid sites in the complex exist, which through computational studies we found to overlap with regions that experience energetic frustration and are less frustrated, respectively. Thus, the residual dynamics in the bound state could be necessary for faster dissociation, which is important for proteins that interact with multiple binding partners. |
| تدمد: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.7b01105 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e1dfe03705535b05e0f080e0b84530b8 https://doi.org/10.1021/acschembio.7b01105 |
| رقم الانضمام: | edsair.doi.dedup.....e1dfe03705535b05e0f080e0b84530b8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548937 15548929 |
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| DOI: | 10.1021/acschembio.7b01105 |