Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex.

Area of Science:

• Oncology
• Molecular Biology
• Biophysics

Background:

• The MYC oncogenic transcription factor drives tumor growth and cancer progression.
• MYC function relies on interactions with cofactors, such as TRRAP.
• Targeting MYC is a key strategy in cancer therapy.

Purpose of the Study:

• To investigate the biophysical states of MYC.
• To characterize the MYC:TRRAP protein-protein interaction (PPI).
• To identify potential therapeutic targets for inhibiting MYC function.

Main Methods:

• Analysis of MYC protein biophysical states.
• Characterization of the MYC:TRRAP interaction interface.
• Structural analysis of the MYC transactivation domain (TAD) and MB2 motif.

Main Results:

• The MYC:TRRAP interaction occurs at the MYC Homology Box 2 (MB2) region within the MYC TAD.
• The inherently disordered MYC TAD, specifically the MB2 motif, may adopt a defined structure upon TRRAP binding.
• This structural change suggests a potential vulnerability for therapeutic intervention.

Conclusions:

• The MYC:TRRAP interaction is crucial for MYC-driven oncogenesis.
• The MB2 motif's unique and conserved nature makes it an attractive target for developing MYC inhibitors.
• Targeting the MYC:TRRAP PPI offers a promising strategy to block cancer progression.