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Cooperative DNA Recognition Modulated by an Interplay between Protein-Protein Interactions and DNA-Mediated Allostery.

Merino F, Bouvier B, Cojocaru V - PLoS Comput. Biol. (2015)

Bottom Line: We found that SOX2 influences the orientation and dynamics of the DNA-bound configuration of OCT4.Further, we estimated the change in OCT4-DNA binding free energy due to the cooperativity with SOX2, observed a good agreement with experimental measurements, and found that SOX2 affects the relative DNA-binding strength of the two OCT4 domains.We consider the OCT4-SOX2 cooperativity as a paradigm of how specificity of transcriptional regulation is achieved through concerted modulation of protein-DNA recognition by different types of interactions.

View Article: PubMed Central - PubMed

Affiliation: Computational Structural Biology Group, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Münster, Germany.

ABSTRACT
Highly specific transcriptional regulation depends on the cooperative association of transcription factors into enhanceosomes. Usually, their DNA-binding cooperativity originates from either direct interactions or DNA-mediated allostery. Here, we performed unbiased molecular simulations followed by simulations of protein-DNA unbinding and free energy profiling to study the cooperative DNA recognition by OCT4 and SOX2, key components of enhanceosomes in pluripotent cells. We found that SOX2 influences the orientation and dynamics of the DNA-bound configuration of OCT4. In addition SOX2 modifies the unbinding free energy profiles of both DNA-binding domains of OCT4, the POU specific and POU homeodomain, despite interacting directly only with the first. Thus, we demonstrate that the OCT4-SOX2 cooperativity is modulated by an interplay between protein-protein interactions and DNA-mediated allostery. Further, we estimated the change in OCT4-DNA binding free energy due to the cooperativity with SOX2, observed a good agreement with experimental measurements, and found that SOX2 affects the relative DNA-binding strength of the two OCT4 domains. Based on these findings, we propose that available interaction partners in different biological contexts modulate the DNA exploration routes of multi-domain transcription factors such as OCT4. We consider the OCT4-SOX2 cooperativity as a paradigm of how specificity of transcriptional regulation is achieved through concerted modulation of protein-DNA recognition by different types of interactions.

No MeSH data available.


Related in: MedlinePlus

Effect of OCT4 and SOX2 binding on the DNA structural properties.(A) Major groove width (B) Minor groove width (C) Axis bending. On the left schematic representations of analyzed properties are drawn. The plots in the middle show the average values with standard errors (see Methods), whereas the plots on the right the inter base pair correlations. The data was collected from the four ensembles of unbiased simulations (free DNA, and SOX2-DNA, OCT4-DNA, OCT4-SOX2-DNA complexes).
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pcbi.1004287.g004: Effect of OCT4 and SOX2 binding on the DNA structural properties.(A) Major groove width (B) Minor groove width (C) Axis bending. On the left schematic representations of analyzed properties are drawn. The plots in the middle show the average values with standard errors (see Methods), whereas the plots on the right the inter base pair correlations. The data was collected from the four ensembles of unbiased simulations (free DNA, and SOX2-DNA, OCT4-DNA, OCT4-SOX2-DNA complexes).

Mentions: To explore the DNA structural changes induced upon binding of OCT4 and SOX2 and how these may contribute to cooperativity and DNA-mediated allostery, we performed two additional ensembles of 1.5 μs unbiased simulations each, one for the SOX2-UTF1 complex and one for the free UTF1 DNA. Each ensemble was composed of 2 independent, 750-ns-long simulations. Then, we analyzed changes in the major (Fig 4A) and minor (Fig 4B) groove widths and axis bending (Fig 4C) in all the simulations relative to the free DNA.


Cooperative DNA Recognition Modulated by an Interplay between Protein-Protein Interactions and DNA-Mediated Allostery.

Merino F, Bouvier B, Cojocaru V - PLoS Comput. Biol. (2015)

Effect of OCT4 and SOX2 binding on the DNA structural properties.(A) Major groove width (B) Minor groove width (C) Axis bending. On the left schematic representations of analyzed properties are drawn. The plots in the middle show the average values with standard errors (see Methods), whereas the plots on the right the inter base pair correlations. The data was collected from the four ensembles of unbiased simulations (free DNA, and SOX2-DNA, OCT4-DNA, OCT4-SOX2-DNA complexes).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4465831&req=5

pcbi.1004287.g004: Effect of OCT4 and SOX2 binding on the DNA structural properties.(A) Major groove width (B) Minor groove width (C) Axis bending. On the left schematic representations of analyzed properties are drawn. The plots in the middle show the average values with standard errors (see Methods), whereas the plots on the right the inter base pair correlations. The data was collected from the four ensembles of unbiased simulations (free DNA, and SOX2-DNA, OCT4-DNA, OCT4-SOX2-DNA complexes).
Mentions: To explore the DNA structural changes induced upon binding of OCT4 and SOX2 and how these may contribute to cooperativity and DNA-mediated allostery, we performed two additional ensembles of 1.5 μs unbiased simulations each, one for the SOX2-UTF1 complex and one for the free UTF1 DNA. Each ensemble was composed of 2 independent, 750-ns-long simulations. Then, we analyzed changes in the major (Fig 4A) and minor (Fig 4B) groove widths and axis bending (Fig 4C) in all the simulations relative to the free DNA.

Bottom Line: We found that SOX2 influences the orientation and dynamics of the DNA-bound configuration of OCT4.Further, we estimated the change in OCT4-DNA binding free energy due to the cooperativity with SOX2, observed a good agreement with experimental measurements, and found that SOX2 affects the relative DNA-binding strength of the two OCT4 domains.We consider the OCT4-SOX2 cooperativity as a paradigm of how specificity of transcriptional regulation is achieved through concerted modulation of protein-DNA recognition by different types of interactions.

View Article: PubMed Central - PubMed

Affiliation: Computational Structural Biology Group, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Münster, Germany.

ABSTRACT
Highly specific transcriptional regulation depends on the cooperative association of transcription factors into enhanceosomes. Usually, their DNA-binding cooperativity originates from either direct interactions or DNA-mediated allostery. Here, we performed unbiased molecular simulations followed by simulations of protein-DNA unbinding and free energy profiling to study the cooperative DNA recognition by OCT4 and SOX2, key components of enhanceosomes in pluripotent cells. We found that SOX2 influences the orientation and dynamics of the DNA-bound configuration of OCT4. In addition SOX2 modifies the unbinding free energy profiles of both DNA-binding domains of OCT4, the POU specific and POU homeodomain, despite interacting directly only with the first. Thus, we demonstrate that the OCT4-SOX2 cooperativity is modulated by an interplay between protein-protein interactions and DNA-mediated allostery. Further, we estimated the change in OCT4-DNA binding free energy due to the cooperativity with SOX2, observed a good agreement with experimental measurements, and found that SOX2 affects the relative DNA-binding strength of the two OCT4 domains. Based on these findings, we propose that available interaction partners in different biological contexts modulate the DNA exploration routes of multi-domain transcription factors such as OCT4. We consider the OCT4-SOX2 cooperativity as a paradigm of how specificity of transcriptional regulation is achieved through concerted modulation of protein-DNA recognition by different types of interactions.

No MeSH data available.


Related in: MedlinePlus