DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
Abstract More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45847-2 |
| _version_ | 1797273912384421888 |
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| author | Sveinn Bjarnason Jordan A. P. McIvor Andreas Prestel Kinga S. Demény Jakob T. Bullerjahn Birthe B. Kragelund Davide Mercadante Pétur O. Heidarsson |
| author_facet | Sveinn Bjarnason Jordan A. P. McIvor Andreas Prestel Kinga S. Demény Jakob T. Bullerjahn Birthe B. Kragelund Davide Mercadante Pétur O. Heidarsson |
| author_sort | Sveinn Bjarnason |
| collection | DOAJ |
| description | Abstract More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET and NMR spectroscopy with molecular simulations showing that DNA binding can lead to complex changes in the IDR ensemble and accessibility. The C-terminal IDR of pioneer factor Sox2 is highly disordered but its conformational dynamics are guided by weak and dynamic charge interactions with the folded DNA binding domain. Both DNA and nucleosome binding induce major rearrangements in the IDR ensemble without affecting DNA binding affinity. Remarkably, interdomain interactions are redistributed in complex with DNA leading to variable exposure of two activation domains critical for transcription. Charged intramolecular interactions allowing for dynamic redistributions may be common in transcription factors and necessary for sensitive tuning of structural ensembles. |
| first_indexed | 2024-03-07T14:50:55Z |
| format | Article |
| id | doaj.art-cf925b9e5d8d4791bf5953ea7b946d44 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:50:55Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-cf925b9e5d8d4791bf5953ea7b946d442024-03-05T19:42:40ZengNature PortfolioNature Communications2041-17232024-02-0115111610.1038/s41467-024-45847-2DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2Sveinn Bjarnason0Jordan A. P. McIvor1Andreas Prestel2Kinga S. Demény3Jakob T. Bullerjahn4Birthe B. Kragelund5Davide Mercadante6Pétur O. Heidarsson7Department of Biochemistry, Science Institute, University of IcelandSchool of Chemical Science, University of AucklandDepartment of Biology, REPIN and Structural Biology and NMR Laboratory, University of CopenhagenDepartment of Biochemistry, Science Institute, University of IcelandDepartment of Theoretical Biophysics, Max Planck Institute of BiophysicsDepartment of Biology, REPIN and Structural Biology and NMR Laboratory, University of CopenhagenSchool of Chemical Science, University of AucklandDepartment of Biochemistry, Science Institute, University of IcelandAbstract More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET and NMR spectroscopy with molecular simulations showing that DNA binding can lead to complex changes in the IDR ensemble and accessibility. The C-terminal IDR of pioneer factor Sox2 is highly disordered but its conformational dynamics are guided by weak and dynamic charge interactions with the folded DNA binding domain. Both DNA and nucleosome binding induce major rearrangements in the IDR ensemble without affecting DNA binding affinity. Remarkably, interdomain interactions are redistributed in complex with DNA leading to variable exposure of two activation domains critical for transcription. Charged intramolecular interactions allowing for dynamic redistributions may be common in transcription factors and necessary for sensitive tuning of structural ensembles.https://doi.org/10.1038/s41467-024-45847-2 |
| spellingShingle | Sveinn Bjarnason Jordan A. P. McIvor Andreas Prestel Kinga S. Demény Jakob T. Bullerjahn Birthe B. Kragelund Davide Mercadante Pétur O. Heidarsson DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2 Nature Communications |
| title | DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2 |
| title_full | DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2 |
| title_fullStr | DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2 |
| title_full_unstemmed | DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2 |
| title_short | DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2 |
| title_sort | dna binding redistributes activation domain ensemble and accessibility in pioneer factor sox2 |
| url | https://doi.org/10.1038/s41467-024-45847-2 |
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