Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site.

Zhenyu Yuan, Bradley D VanderWielen, Benedetto Daniele Giaimo, Leiling Pan, Courtney E Collins, Aleksandra Turkiewicz, Kerstin Hein, Franz Oswald, Tilman Borggrefe, Rhett A Kovall

Cell reports 2019 Jan 22

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Notch is a conserved signaling pathway that is essential for metazoan development and homeostasis; dysregulated signaling underlies the pathophysiology of numerous human diseases. Receptor-ligand interactions result in gene expression changes, which are regulated by the transcription factor RBPJ. RBPJ forms a complex with the intracellular domain of the Notch receptor and the coactivator Mastermind to activate transcription, but it can also function as a repressor by interacting with corepressor proteins. Here, we determine the structure of RBPJ bound to the corepressor SHARP and DNA, revealing its mode of binding to RBPJ. We tested structure-based mutants in biophysical and biochemical-cellular assays to characterize the role of RBPJ as a repressor, clearly demonstrating that RBPJ mutants deficient for SHARP binding are incapable of repressing transcription of genes responsive to Notch signaling in cells. Altogether, our structure-function studies provide significant insights into the repressor function of RBPJ. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Zhenyu Yuan, Bradley D VanderWielen, Benedetto Daniele Giaimo, Leiling Pan, Courtney E Collins, Aleksandra Turkiewicz, Kerstin Hein, Franz Oswald, Tilman Borggrefe, Rhett A Kovall. Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site. Cell reports. 2019 Jan 22;26(4):845-854.e6