Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP

Serena Muratcioglu, Diego M Presman, John R Pooley, Lars Grøntved, Gordon L Hager, Ruth Nussinov, Ozlem Keskin, Attila Gursoy

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPα homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPα. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.

Original languageEnglish
JournalBiophysical Journal
Volume109
Issue number6
Pages (from-to)1227-39
Number of pages13
ISSN0006-3495
DOIs
Publication statusPublished - 15. Sep 2015

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Chromatin Assembly and Disassembly
Glucocorticoid Receptors
Mutation
Proteins
Leucine
Computer Simulation

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Muratcioglu, S., Presman, D. M., Pooley, J. R., Grøntved, L., Hager, G. L., Nussinov, R., ... Gursoy, A. (2015). Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP. Biophysical Journal, 109(6), 1227-39. https://doi.org/10.1016/j.bpj.2015.06.044
Muratcioglu, Serena ; Presman, Diego M ; Pooley, John R ; Grøntved, Lars ; Hager, Gordon L ; Nussinov, Ruth ; Keskin, Ozlem ; Gursoy, Attila. / Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP. In: Biophysical Journal. 2015 ; Vol. 109, No. 6. pp. 1227-39.
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title = "Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP",
abstract = "The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPα homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPα. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.",
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Muratcioglu, S, Presman, DM, Pooley, JR, Grøntved, L, Hager, GL, Nussinov, R, Keskin, O & Gursoy, A 2015, 'Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP', Biophysical Journal, vol. 109, no. 6, pp. 1227-39. https://doi.org/10.1016/j.bpj.2015.06.044

Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP. / Muratcioglu, Serena; Presman, Diego M; Pooley, John R; Grøntved, Lars; Hager, Gordon L; Nussinov, Ruth; Keskin, Ozlem; Gursoy, Attila.

In: Biophysical Journal, Vol. 109, No. 6, 15.09.2015, p. 1227-39.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Structural Modeling of GR Interactions with the SWI/SNF Chromatin Remodeling Complex and C/EBP

AU - Muratcioglu, Serena

AU - Presman, Diego M

AU - Pooley, John R

AU - Grøntved, Lars

AU - Hager, Gordon L

AU - Nussinov, Ruth

AU - Keskin, Ozlem

AU - Gursoy, Attila

N1 - Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.

PY - 2015/9/15

Y1 - 2015/9/15

N2 - The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPα homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPα. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.

AB - The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPα homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPα. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.

U2 - 10.1016/j.bpj.2015.06.044

DO - 10.1016/j.bpj.2015.06.044

M3 - Journal article

C2 - 26278180

VL - 109

SP - 1227

EP - 1239

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 6

ER -