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

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• Over 1600 human transcription factors regulate gene expression and cell fate.
• Intrinsically disordered regions (IDRs) are key functional elements but lack structural models, hindering mechanistic understanding.

Purpose of the Study:

• To investigate the impact of DNA binding on the structural ensemble and accessibility of transcription factor IDRs.
• To decode the mechanism of pioneer factor Sox2's intrinsically disordered C-terminal region.

Main Methods:

• Integration of single-molecule Förster Resonance Energy Transfer (smFRET) and Nuclear Magnetic Resonance (NMR) spectroscopy.
• Utilizing molecular simulations to model conformational dynamics.
• Analysis of DNA and nucleosome binding effects on Sox2's structure and function.

Main Results:

• DNA binding induces significant rearrangements in the IDR ensemble and accessibility without altering DNA binding affinity.
• Sox2's C-terminal IDR, though disordered, exhibits dynamics influenced by charge interactions with its DNA binding domain.
• Interdomain interactions redistribute upon DNA binding, modulating the exposure of critical activation domains.

Conclusions:

• Dynamic charge interactions within transcription factors are crucial for tuning structural ensembles.
• Rearrangements in IDRs upon DNA/nucleosome binding are essential for precise control of transcriptional activity.
• The study provides a mechanistic framework for understanding transcription factor regulation via IDRs.