Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site. Yuan, Z., VanderWielen, B. D., Giaimo, B. D., Pan, L., Collins, C. E., Turkiewicz, A., Hein, K., Oswald, F., Borggrefe, T., & Kovall, R. A. Cell Reports, 26(4):845–854.e6, 2019. doi abstract bibtex 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.
@article{yuan_structural_2019,
title = {Structural and {Functional} {Studies} of the {RBPJ}-{SHARP} {Complex} {Reveal} a {Conserved} {Corepressor} {Binding} {Site}},
volume = {26},
issn = {2211-1247},
doi = {10.1016/j.celrep.2018.12.097},
abstract = {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.},
language = {eng},
number = {4},
journal = {Cell Reports},
author = {Yuan, Zhenyu and VanderWielen, Bradley D. and Giaimo, Benedetto Daniele and Pan, Leiling and Collins, Courtney E. and Turkiewicz, Aleksandra and Hein, Kerstin and Oswald, Franz and Borggrefe, Tilman and Kovall, Rhett A.},
year = {2019},
pmid = {30673607},
pmcid = {PMC6352735},
keywords = {Animals, Binding Sites, CSL, DNA, DNA-Binding Proteins, HEK293 Cells, HeLa Cells, Humans, Immunoglobulin J Recombination Signal Sequence-Binding Protein, MINT, Mice, Multiprotein Complexes, Notch signaling, Protein Structure, Quaternary, RBPJ, RNA-Binding Proteins, Receptors, Notch, SHARP, SPEN, Signal Transduction, Transcription, Genetic, X-ray crystallography, isothermal titration calorimetry, signal transduction, transcriptional regulation},
pages = {845--854.e6},
}
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