An order-to-disorder structural switch activates the FoxM1 transcription factor

Area of Science:

• Molecular biology
• Structural biology
• Gene regulation

Background:

• Transcription factors utilize intrinsically disordered transactivation domains (TADs) that gain structure upon binding co-regulators.
• Negative regulatory domains (NRDs) often suppress TAD activity through autoregulation.

Purpose of the Study:

• To determine the solution structure of the autoinhibited complex between the NRD and TAD of FoxM1.
• To elucidate the mechanism of FoxM1 regulation by kinases and co-activator binding.

Main Methods:

• Nuclear magnetic resonance (NMR) spectroscopy to determine the solution structure of the FoxM1 NRD-TAD complex.
• Biochemical assays to investigate the role of kinases (Plk1, Cdk) and co-activator binding (CBP).

Main Results:

• The intrinsically disordered FoxM1 NRD and TAD associate to form a structured, autoinhibited complex.
• Phosphorylation by Plk1 and Cdk releases the TAD into a disordered state.
• The released TAD then binds to the TAZ2 or KIX domains of the transcriptional co-activator CBP.

Conclusions:

• FoxM1 activity is regulated by a conformational switch mechanism involving its NRD and TAD.
• Kinase-mediated phosphorylation controls the transition of the TAD between disordered and ordered states, enabling co-activator interaction and gene activation.