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DNA controls the dimerization of the human FoxP1 forkhead domain
Narendar Kolimi1, Jake Ballard1, Thomas Peulen2
1Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA.
Cell Reports. Physical Science
|April 8, 2024
Summary
DNA binding destabilizes the FoxP1 protein, impacting gene regulation. This suggests FoxP1
Area of Science:
- Molecular biology
- Biophysics
- Genetics
Background:
- Transcription factors (TFs) control gene expression by binding DNA.
- The molecular impact of DNA on TF structure and function remains poorly understood.
- FoxP1 is a transcription factor involved in gene regulation.
Purpose of the Study:
- To investigate the molecular effect of DNA on the structure and stability of the human FoxP1 forkhead (FKH) domain.
- To elucidate the mechanism of DNA-mediated regulation of FoxP1 function.
Main Methods:
- Single-molecule multiparameter fluorescence spectroscopy
- Molecular dynamics simulations
- Biochemical assays
Main Results:
- The monomeric FKH domain of human FoxP1 is disordered.
- Dimerization increases the folded population of the FKH domain.
- DNA binding induces a disordered FKH dimer bound to DNA.
- DNA binding negatively impacts the stability of the dimeric FoxP1:DNA complex.
Conclusions:
- DNA binding reversibly regulates FKH dimers, suggesting unstable FoxP1-dependent gene suppression.
- Additional dimerization domains or cofactors may be required to counteract the DNA's negative impact on FoxP1 stability and function.
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