A Switch between Two Intrinsically Disordered Conformational Ensembles Modulates the Active Site of a
Giuseppe Sicoli1, Thomas Kress2, Hervé Vezin1
1Laboratoire Avancé de Spectroscopie pour les Interactions, la Réactivité et l'Environnement (LASIRE), UMR CNRS 8516, Université de Lille, Avenue Paul Langevin - C4, F-59655 Villeneuve d'Ascq, France.
The Journal of Physical Chemistry Letters
|October 8, 2020
Summary
Transcription factors like MAX utilize intrinsically disordered regions to switch between flexible and hinged states, enabling dynamic DNA binding. This plasticity is key for their function in cell regulation.
Area of Science:
- Molecular Biology
- Biophysics
- Structural Biology
Background:
- Transcription factors regulate gene expression and are crucial for cell function.
- Intrinsically disordered proteins (IDPs) lack stable structures but exhibit functional plasticity.
- Proto-oncogenic basic-helix-loop-helix (bHLH) transcription factors, including MAX, play vital roles but their disordered DNA-binding domains are challenging to study.
Purpose of the Study:
- To investigate the structural dynamics of the intrinsically disordered DNA-binding site of the transcription factor MAX.
- To understand how conformational flexibility in MAX influences its DNA-binding capabilities.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy.
- Molecular Dynamics (MD) simulations.
- Electron Paramagnetic Resonance (EPR) measurements.
Main Results:
- The free MAX2 homodimer samples two distinct intrinsically disordered conformational subensembles.
- One subensemble comprises flexible, extended conformers, while the second exhibits 'hinged' conformations where N-terminal tails interact with the HLH region.
- These distinct states expose the DNA-binding site differently, suggesting mechanisms for DNA recruitment and binding.
Conclusions:
- Intrinsically disordered domains confer evolutionary advantages through conformational plasticity.
- MAX2's disordered DNA-binding site dynamically switches between states, modulating DNA complex formation.
- This conformational switching enhances DNA ligand recruitment and binding affinity.
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