Limits...
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

Orientational dynamics in DNA-bound configurations.(A,B) Schematic view of the coordinate system (A) and definition (B) of the Rock and Tumble angles describing the orientation of the docking helices (shown as opaque cartoons) of the two domains of OCT4. Rock-Tumble histograms in the absence (C,D) or presence (E,F) of SOX2 for the POUS (C,E) and POUHD (D,F). See also S3 Fig.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4465831&req=5

pcbi.1004287.g002: Orientational dynamics in DNA-bound configurations.(A,B) Schematic view of the coordinate system (A) and definition (B) of the Rock and Tumble angles describing the orientation of the docking helices (shown as opaque cartoons) of the two domains of OCT4. Rock-Tumble histograms in the absence (C,D) or presence (E,F) of SOX2 for the POUS (C,E) and POUHD (D,F). See also S3 Fig.

Mentions: To explore the dynamics of the POUS and POUHD domains relative to their binding sites, we calculated the orientation of the docking helices (Fig 1A) around the helical axis (Rock) and inside the binding groove (Tumble) (Fig 2A and 2B). Consistent with the small number of recurrent POUHD-DNA contacts observed in the absence of SOX2 (Fig 1B, S1 Table), the binding orientation of the POUHD fluctuates more than that of the POUS (Fig 2C and 2D). When SOX2 is present, there is a 14% decrease in the fluctuation of the POUS orientation (S2 Table) calculated from the distributions of the Rock and Tumble angles (Fig 2C and 2E). However, the effect of SOX2 on the POUS orientation and dynamics is subtle and further sampling may be necessary for its correct quantification. In addition, SOX2 induces a reorientation and a decrease in the dynamics of the POUHD (Fig 2D and 2F). The diagonal pattern in the Rock versus Tumble histogram (Fig 2F) suggests that SOX2 couples the motion of the POUHD to the major groove of the DNA, reflecting the increased number of protein-DNA interactions of the globular region of the POUHD in the presence of SOX2 (Fig 1B, S1 Table). Importantly, these results were found to be consistent in all individual simulations from the ensembles (S3 Fig).


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)

Orientational dynamics in DNA-bound configurations.(A,B) Schematic view of the coordinate system (A) and definition (B) of the Rock and Tumble angles describing the orientation of the docking helices (shown as opaque cartoons) of the two domains of OCT4. Rock-Tumble histograms in the absence (C,D) or presence (E,F) of SOX2 for the POUS (C,E) and POUHD (D,F). See also S3 Fig.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004287.g002: Orientational dynamics in DNA-bound configurations.(A,B) Schematic view of the coordinate system (A) and definition (B) of the Rock and Tumble angles describing the orientation of the docking helices (shown as opaque cartoons) of the two domains of OCT4. Rock-Tumble histograms in the absence (C,D) or presence (E,F) of SOX2 for the POUS (C,E) and POUHD (D,F). See also S3 Fig.
Mentions: To explore the dynamics of the POUS and POUHD domains relative to their binding sites, we calculated the orientation of the docking helices (Fig 1A) around the helical axis (Rock) and inside the binding groove (Tumble) (Fig 2A and 2B). Consistent with the small number of recurrent POUHD-DNA contacts observed in the absence of SOX2 (Fig 1B, S1 Table), the binding orientation of the POUHD fluctuates more than that of the POUS (Fig 2C and 2D). When SOX2 is present, there is a 14% decrease in the fluctuation of the POUS orientation (S2 Table) calculated from the distributions of the Rock and Tumble angles (Fig 2C and 2E). However, the effect of SOX2 on the POUS orientation and dynamics is subtle and further sampling may be necessary for its correct quantification. In addition, SOX2 induces a reorientation and a decrease in the dynamics of the POUHD (Fig 2D and 2F). The diagonal pattern in the Rock versus Tumble histogram (Fig 2F) suggests that SOX2 couples the motion of the POUHD to the major groove of the DNA, reflecting the increased number of protein-DNA interactions of the globular region of the POUHD in the presence of SOX2 (Fig 1B, S1 Table). Importantly, these results were found to be consistent in all individual simulations from the ensembles (S3 Fig).

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