Intrinsically Disordered Regions in the Transcription Factor MYC:MAX Modulate DNA Binding via Intramolecular...

Area of Science:

• Molecular Biology
• Protein Dynamics
• Transcription Factor Regulation

Background:

• MYC is a key transcription factor regulating cell cycle, metabolism, and apoptosis.
• MYC function is primarily regulated by interactions with other proteins.
• MYC is a largely intrinsically disordered oncoprotein that forms a complex with MAX.

Purpose of the Study:

• To investigate the role of intramolecular interactions in MYC regulation.
• To identify and map binding sites for the MYC:MAX DNA-binding domain on MYC's intrinsically disordered regions.
• To understand how these intramolecular interactions affect MYC's DNA binding.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy to map binding sites.
• Surface Plasmon Resonance (SPR) to study binding kinetics.
• Preparation of recombinant full-length MYC:MAX complex.

Main Results:

• Multiple binding sites for the MYC:MAX DNA-binding domain were identified on MYC's intrinsically disordered regions.
• Intramolecular interactions are driven by electrostatic attraction and exhibit distinct affinities.
• These interactions are competitive with DNA binding, particularly involving MYC box 0 (Mb0).
• Intramolecular interactions decelerate the association of MYC:MAX complexes with DNA.

Conclusions:

• MYC is regulated by intramolecular interactions within its intrinsically disordered regions.
• These interactions modulate MYC's DNA-binding activity, impacting gene regulation.
• The findings provide new insights into bHLH-LZ TF regulation and potential drug targets.