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

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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.
TidsskriftNature Communications
Udgave nummer1
Antal sider16
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank Benjamin Schuler and Daniel Nettels for support using the data analysis toolbox Fretica. We thank Beat Fierz for technical assistance with nucleosome preparation. We thank Magnús Kristjánsson, Erna Magnúsdóttir, and Erik Holmstrom for stimulating discussions, and Matthías Valdimarsson, Sarah Ruidiaz, and Mahtab Hafizi for technical assistance. This work was supported by funding from the European Research Council (ERC StG, 101040601-PIONEER, to P.O.H.), the Icelandic Research Fund (grant nr. 2659105, to P.O.H.), the University of Iceland Doctoral Fund (to S.B.), the Max Planck Society (to J.T.B.), the University of Auckland (to J.A.P.M.), the Novo Nordisk Foundation to the Challenge centre REPIN (#NNF18OC0033926 to B.B.K.), and by cOpenNMR, an infrastructure granted from the Novo Nordisk Foundation (#NNF18OC0032996).

Publisher Copyright:
© The Author(s) 2024.

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