Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding.

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• The Myc protein is a crucial oncoprotein regulating cell growth, differentiation, and apoptosis.
• Understanding the molecular mechanisms of Myc function is essential due to its role in cancer.
• The N-terminal region of c-Myc is vital for mediating protein interactions involved in cellular processes.

Purpose of the Study:

• To characterize the intrinsically disordered properties of the Myc N-terminal region (Myc-1-88).
• To investigate the role of hierarchical phosphorylation at S62 and T58 in Myc protein regulation.
• To elucidate the interaction of Myc with Bin1 and its impact on conformational dynamics.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy for chemical shift analysis, relaxation measurements, and NOE analysis.
• Surface Plasmon Resonance (SPR) to assay protein-protein interactions.
• Characterization of intrinsically disordered protein regions.

Main Results:

• Myc-1-88 exhibits a heterogeneous conformational space with transiently structured regions (residues 22-33 and Myc homology box I, residues 45-65).
• These structured regions are conserved across the Myc family.
• Bin1 binds to the S62 region of Myc-1-88, forming a dynamically disordered complex and altering intramolecular dynamics.

Conclusions:

• Intrinsically disordered regions play a significant role in mediating transient interactions for Myc, a key transcriptional regulator.
• Phosphorylation at S62 and T58 is critical for regulating Myc protein stability and function.
• These findings enhance the understanding of Myc's multifaceted role in gene regulation and have implications for cancer research.