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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.


Interactions with the DNA of the remained-bound domain.(A,B) Change in recurrent (A) and non-stable (B) POUS-DNA contacts when pulling the POUHD. (C-F) Change in recurrent (C,E) and non-stable (D,F) contacts between the globular region (C,D) and the N-terminal tail (E,F) of the POUHD when pulling the POUS. The fraction of recurrent contacts defined as in Fig 4. See also S5 Fig.
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pcbi.1004287.g006: Interactions with the DNA of the remained-bound domain.(A,B) Change in recurrent (A) and non-stable (B) POUS-DNA contacts when pulling the POUHD. (C-F) Change in recurrent (C,E) and non-stable (D,F) contacts between the globular region (C,D) and the N-terminal tail (E,F) of the POUHD when pulling the POUS. The fraction of recurrent contacts defined as in Fig 4. See also S5 Fig.

Mentions: Next, we analyzed the effect of the unbinding of one domain of OCT4 on the domain that remained bound to DNA (Fig 6). The unbinding of the POUHD has no impact on the number of recurrent or non-stable contacts of the POUS (Fig 6A and 6B). On the other hand, the unbinding of the POUS has a strong effect on the DNA interaction of the globular region of the POUHD when SOX2 is present (Fig 6C and 6D). A significant decrease in the number of recurrent interactions is accompanied by an increase in non-stable interactions. This suggests that the POUHD is reorienting, but not detaching from the DNA. Indeed, the analysis of the Rock and Tumble angles during dissociation further confirms this (S5 Fig). Importantly, the absence of this phenomenon in the simulation of the OCT4-UTF1 complex suggests that this reorientation is induced by the allosteric communication between the POUHD and SOX2. Conversely, the unbinding of the POUS does not affect the number of recurrent and non-stable contacts between the POUHD tail and the DNA (Fig 6E and 6F).


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)

Interactions with the DNA of the remained-bound domain.(A,B) Change in recurrent (A) and non-stable (B) POUS-DNA contacts when pulling the POUHD. (C-F) Change in recurrent (C,E) and non-stable (D,F) contacts between the globular region (C,D) and the N-terminal tail (E,F) of the POUHD when pulling the POUS. The fraction of recurrent contacts defined as in Fig 4. See also S5 Fig.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004287.g006: Interactions with the DNA of the remained-bound domain.(A,B) Change in recurrent (A) and non-stable (B) POUS-DNA contacts when pulling the POUHD. (C-F) Change in recurrent (C,E) and non-stable (D,F) contacts between the globular region (C,D) and the N-terminal tail (E,F) of the POUHD when pulling the POUS. The fraction of recurrent contacts defined as in Fig 4. See also S5 Fig.
Mentions: Next, we analyzed the effect of the unbinding of one domain of OCT4 on the domain that remained bound to DNA (Fig 6). The unbinding of the POUHD has no impact on the number of recurrent or non-stable contacts of the POUS (Fig 6A and 6B). On the other hand, the unbinding of the POUS has a strong effect on the DNA interaction of the globular region of the POUHD when SOX2 is present (Fig 6C and 6D). A significant decrease in the number of recurrent interactions is accompanied by an increase in non-stable interactions. This suggests that the POUHD is reorienting, but not detaching from the DNA. Indeed, the analysis of the Rock and Tumble angles during dissociation further confirms this (S5 Fig). Importantly, the absence of this phenomenon in the simulation of the OCT4-UTF1 complex suggests that this reorientation is induced by the allosteric communication between the POUHD and SOX2. Conversely, the unbinding of the POUS does not affect the number of recurrent and non-stable contacts between the POUHD tail and the DNA (Fig 6E and 6F).

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.