Structural and Functional Studies of the RBPJ-SHARP Complex Reveal a Conserved Corepressor Binding Site.
Animals
Binding Sites
DNA
/ chemistry
DNA-Binding Proteins
/ chemistry
HEK293 Cells
HeLa Cells
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein
/ chemistry
Mice
Multiprotein Complexes
/ chemistry
Protein Structure, Quaternary
RNA-Binding Proteins
/ chemistry
Receptors, Notch
/ chemistry
Signal Transduction
Transcription, Genetic
CSL
MINT
Notch signaling
RBPJ
SHARP
SPEN
X-ray crystallography
isothermal titration calorimetry
signal transduction
transcriptional regulation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
22 01 2019
22 01 2019
Historique:
received:
31
05
2018
revised:
05
11
2018
accepted:
21
12
2018
entrez:
24
1
2019
pubmed:
24
1
2019
medline:
7
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30673607
pii: S2211-1247(18)32057-6
doi: 10.1016/j.celrep.2018.12.097
pmc: PMC6352735
mid: NIHMS1519366
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Immunoglobulin J Recombination Signal Sequence-Binding Protein
0
Multiprotein Complexes
0
RNA-Binding Proteins
0
Rbpj protein, mouse
0
Receptors, Notch
0
Spen protein, mouse
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
845-854.e6Subventions
Organisme : NCI NIH HHS
ID : R01 CA178974
Pays : United States
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.