Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2023

DNA binding enhances activation domain accessibility in pioneer factor Sox2

Höfundar / Authors: Sveinn Bjarnason (1), Jordan McIvor (2), Andreas Prestel (3), Kinga S. Demény (1), Jakob T. Bullerjahn (4), Birthe B. Kragelund (3), Davide Mercadante (2), Pétur O. Heiðarsson (1).

Starfsvettvangur / Affiliations: 1. Department of Biochemistry, Science Institute, University of Iceland. 2. School of Chemical Science, University of Auckland, Auckland, New Zealand. 3. Structural biology and NMR Laboratory, Department of Biology, Faculty of Science, University of Copenhagen. 4. Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Germany.

Kynnir / Presenter: Sveinn Bjarnason

More than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell decisions. Transcription factor function is conveyed through intrinsically disordered effector domains yet descriptions of their conformational ensembles and how they are modulated by DNA binding are largely missing. Here we reconstruct the free and DNA-bound ensembles of full-length pioneer transcription factor Sox2, by integrating single-molecule FRET and NMR spectroscopy with molecular simulations, and demonstrate that DNA binding can lead to surprisingly complex changes in effector domain architecture. The ~200 residue-long C-terminal effector domain of Sox2 is highly disordered and dynamic but its conformational properties are sensitively guided by weak electrostatic interactions with the structured DNA binding domain. DNA or nucleosome binding induces a major rearrangement in the effector domain structural ensemble yet without affecting binding affinity. Remarkably, interdomain interactions are redistributed in the complex which specifically modulates the accessibility of the transcriptional activation domains. General sequence features of transcription factors indicate that transient and charge-driven interactions between domains are common, enabling sensitive tuning of activation domain accessibility without necessarily compromising DNA binding affinity.