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Domain tethering impacts dimerization and DNA-mediated allostery in the human transcription factor FoxP1
Perla Cruz1, Nicolás Paredes1, Isabel Asela1
1Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Casilla 653, Santiago 7800003, Chile.
The Journal of Chemical Physics
|May 15, 2023
Summary
The disordered linker in FoxP1 transcription factors influences dimerization and DNA binding. DNA binding allosterically reduces FoxP1 dimerization, with the linker playing a key role in gene regulation.
Area of Science:
- Molecular biology
- Biophysics
- Structural biology
Background:
- Transcription factors are key regulators of gene expression.
- The human FoxP subfamily comprises multidomain proteins with DNA-binding and regulatory functions.
- FoxP proteins contain a Leucine Zipper (ZIP) and a Forkhead (FKH) domain, linked by a disordered region.
Purpose of the Study:
- To investigate how domain tethering in FoxP1 affects ZIP and FKH domain dimerization.
- To understand the allosteric regulation of FoxP1 dimerization by DNA binding.
- To elucidate the role of the interdomain linker in FoxP1 structure and function.
Main Methods:
- Replica exchange discrete molecular dynamics simulations.
- Single-molecule fluorescence experiments.
- Biophysical characterization techniques.
Main Results:
- Domain tethering in FoxP1 promotes dimerization but inhibits FKH domain swapping.
- The linker region mediates dynamic interactions between ZIP and FKH domains, forming open and closed states.
- DNA binding allosterically reduces FoxP1 dimerization propensity.
Conclusions:
- The interdomain linker is crucial for organizing and regulating the dynamics of multidomain transcription factors like FoxP1.
- DNA binding induces structural changes that modulate FoxP1 dimerization, highlighting the linker's role in gene regulation.
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