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DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2

Author

Listed:
  • Sveinn Bjarnason

    (University of Iceland)

  • Jordan A. P. McIvor

    (University of Auckland)

  • Andreas Prestel

    (University of Copenhagen)

  • Kinga S. Demény

    (University of Iceland)

  • Jakob T. Bullerjahn

    (Max Planck Institute of Biophysics)

  • Birthe B. Kragelund

    (University of Copenhagen)

  • Davide Mercadante

    (University of Auckland)

  • Pétur O. Heidarsson

    (University of Iceland)

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.

Suggested Citation

  • Sveinn Bjarnason & Jordan A. P. McIvor & Andreas Prestel & Kinga S. Demény & Jakob T. Bullerjahn & Birthe B. Kragelund & Davide Mercadante & Pétur O. Heidarsson, 2024. "DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45847-2
    DOI: 10.1038/s41467-024-45847-2
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    1. Bikash Chandra Swain & Pascale Sarkis & Vanessa Ung & Sabrina Rousseau & Laurent Fernandez & Ani Meltonyan & V. Esperance Aho & Davide Mercadante & Cameron D. Mackereth & Mikayel Aznauryan, 2024. "Disordered regions of human eIF4B orchestrate a dynamic self-association landscape," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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