Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor...

Area of Science:

• Structural biology
• Biochemistry
• Cancer research

Background:

• Investigating regulatory mechanisms of intrinsically disordered proteins (IDPs) is challenging due to their structural heterogeneity.
• The transcriptional corepressor CtBP interacts with proteins like RAI2 via Short Linear Motifs (SLiMs).

Purpose of the Study:

• To elucidate the structural and functional mechanisms of CtBP regulation by the disordered protein RAI2.
• To explore the role of RAI2-mediated CtBP regulation in cancer, specifically prostate cancer.

Main Methods:

• Integrative structural biology approach combining cryo-electron microscopy.
• Biophysical characterization of CtBP-RAI2 interactions.
• Analysis of prostate cancer patient cohorts.

Main Results:

• RAI2 induces CtBP polymerization into filaments of stacked tetrameric CtBP layers.
• These filaments form nuclear foci, leading to the relief of CtBP's corepressor function in cancer cells.
• RAI2 levels are significantly decreased in advanced, treatment-resistant prostate cancer subtypes.

Conclusions:

• RAI2-mediated multivalent interactions drive CtBP polymerization, impacting its function.
• This mechanism offers a paradigm for how disordered proteins regulate cellular processes and disease.
• Reduced RAI2 expression correlates with aggressive prostate cancer, suggesting its tumor-suppressive role.