期刊
CELL REPORTS
卷 26, 期 4, 页码 845-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.12.097
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类别
资金
- NIH [5R01CA178974]
- DFG (German Research Foundation) [TRR81, BO 1639/9-1]
- Excellence Cluster for Cardio Pulmonary System (ECCPS) in Giessen
- University Medical Center Giessen and Marburg (UKGM)
- DFG [SFB1074/A3, GRK 2253 - HEIST]
- BMBF (Federal Ministry of Education and Research, Research Nucleus SyStAR)
- DOE Office of Science [DE-AC02-06CH11357]
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.
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