Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2

Goradia N. et al.

While the elucidation of regulatory mechanisms of folded proteins is facilitated due to their amenability to high-resolution structural characterization, investigation of these mechanisms in disordered proteins is more challenging due to their structural heterogeneity, which can be captured by a variety of biophysical approaches. Here, we used the transcriptional master corepressor CtBP, which binds the putative metastasis suppressor RAI2 through repetitive SLiMs, as a model system. Using cryo-electron microscopy embedded in an integrative structural biology approach, we show that RAI2 unexpectedly induces CtBP polymerization through filaments of stacked tetrameric CtBP layers. These filaments lead to RAI2-mediated CtBP nuclear foci and relieve its corepressor function in RAI2-expressing cancer cells. The impact of RAI2-mediated CtBP loss-of-function is illustrated by the analysis of a diverse cohort of prostate cancer patients, which reveals a substantial decrease in RAI2 in advanced treatment-resistant cancer subtypes. As RAI2-like SLiM motifs are found in a wide range of organisms, including pathogenic viruses, our findings serve as a paradigm for diverse functional effects through multivalent interaction-mediated polymerization by disordered proteins in healthy and diseased conditions.


Share this article

June, 2024


Products used in this publication

  • ChIP-seq Grade
    EZH2 Antibody
  • ChIP-seq Grade
    H3K27me3 Antibody
  • Mouse IgG
    Mouse IgG (sample size)
  • Mouse IgG
    Rabbit IgG


  • FASEB Biological Methylation: Fundamental Mechanisms
    Porto, Portugal
    Jul 28-Aug 1, 2024
 See all events


       Site map   |   Contact us   |   Conditions of sales   |   Conditions of purchase   |   Privacy policy