TY - JOUR

T1 - DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2

AU - Bjarnason, Sveinn

AU - McIvor, Jordan A.P.

AU - Prestel, Andreas

AU - Demény, Kinga S.

AU - Bullerjahn, Jakob T.

AU - Kragelund, Birthe B.

AU - Mercadante, Davide

AU - Heidarsson, Pétur O.

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-024-45847-2

DO - 10.1038/s41467-024-45847-2

M3 - Journal article

C2 - 38365983

AN - SCOPUS:85185265027

VL - 15

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1445

ER -