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PMID: 18155729 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mutational and energetic studies of Notch 1 transcription complexes.

Journal of molecular biology ·Vol. 376 ·No. 1 ·2008-02-08 ·Pages 131-40

Del Bianco C, Aster JC, Blacklow SC

Abstract

Notch proteins constitute the receptors of a highly conserved signaling pathway that influences cell fate decisions both during development and in adulthood. A proteolytic cascade induced by ligand stimulation results in release of the intracellular Notch domain from the cell membrane, allowing it to enter the nucleus and form a complex with a DNA-bound transcription factor called CSL (CBF-1/RBP-J kappa, Suppressor of Hairless, and Lag-1) and a coactivator of the Mastermind family. Assembly of this Notch nuclear complex is the key step in the transcriptional response to a Notch signal. In the studies reported here, we mapped residues important for the stabilization of this multiprotein-DNA complex using site-directed mutagenesis, determined the affinity of the three-domain form of CSL for its various partners, and investigated sources of cooperativity in complex formation by monitoring the influence of various components of the complex on the interactions of CSL with its other partners. Our findings are consistent with a model for complex assembly in which the RBP-J kappa-associated molecule domain of Notch increases the effective concentration of the ankyrin domain for its binding site on the Rel-homology region of CSL, enabling docking of the ankyrin domain and subsequent recruitment of the Mastermind-like coactivator.

MeSH Terms
Amino Acid Substitution Cell Line DNA/metabolism DNA-Binding Proteins/metabolism Humans Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism Models, Molecular Mutagenesis, Site-Directed Nuclear Proteins/metabolism Protein Binding Receptor, Notch1/chemistry,genetics,metabolism Trans-Activators Transcription Factors
Chemicals
DNA-Binding Proteins Immunoglobulin J Recombination Signal Sequence-Binding Protein MAML1 protein, human NOTCH1 protein, human Nuclear Proteins RBPJ protein, human Receptor, Notch1 Trans-Activators Transcription Factors DNA
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Del Bianco Cristina
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Aster Jon C
Blacklow Stephen C
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Article Info
Journal
Journal of molecular biology
Abbr.
J Mol Biol
ISSN
1089-8638
DOI
10.1016/j.jmb.2007.11.061
Published
2008-02-08
Epub
2007-00-28
Pages
131-40
Language
English
Region
England
NLM ID
2985088R
PMCID
PMC2766816
Subset
IM
Grants
NCI NIH HHS · P01 CA119070-01A1 · United States
NCI NIH HHS · P01 CA119070-01A10003 · United States
NCI NIH HHS · R01 CA092433 · United States
NCI NIH HHS · P01 CA119070-029001 · United States
NCI NIH HHS · P01 CA119070-020003 · United States
NCI NIH HHS · R01 CA092433-05 · United States
NCI NIH HHS · R01 CA119130 · United States
NCI NIH HHS · R01 CA119130-01 · United States
NCI NIH HHS · R01 CA092433-03 · United States
NCI NIH HHS · P01 CA119070-01A19001 · United States
NCI NIH HHS · R01 CA092433-04 · United States
NCI NIH HHS · P01 CA119070 · United States
External Links
PubMed source DOI: 10.1016/j.jmb.2007.11.061 PMC Full Text View journal details
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