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

Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Sarah Greimeier, Lina Bergmann, Andras Lang, Haydyn Mertens, Aleksandra Węglarz, Simon Sander, Grzegorz Chojnowski, Harriet Wikman, Oliver Ohlenschläger, Gunhild Amsberg, Klaus Pantel () and Matthias Wilmanns ()
Additional contact information
Nishit Goradia: Hamburg Unit
Stefan Werner: University Cancer Center Hamburg
Edukondalu Mullapudi: Hamburg Unit
Sarah Greimeier: University Cancer Center Hamburg
Lina Bergmann: University Cancer Center Hamburg
Andras Lang: Fritz-Lipmann-Institute
Haydyn Mertens: Hamburg Unit
Aleksandra Węglarz: University Cancer Center Hamburg
Simon Sander: University Cancer Center Hamburg
Grzegorz Chojnowski: Hamburg Unit
Harriet Wikman: University Cancer Center Hamburg
Oliver Ohlenschläger: Fritz-Lipmann-Institute
Gunhild Amsberg: Martini Clinic
Klaus Pantel: University Cancer Center Hamburg
Matthias Wilmanns: Hamburg Unit

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49488-3

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