The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3.

Animals Humans DNA-Binding Proteins / metabolism Epigenesis, Genetic Gene Expression Regulation Histone Demethylases / genetics Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics Intracellular Signaling Peptides and Proteins / genetics LIM Domain Proteins / metabolism Muscle Proteins / genetics Protein Binding Receptors, Notch / genetics

Journal

Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011

Informations de publication

Date de publication:
09 12 2022
Historique:
accepted: 14 11 2022
revised: 01 10 2022
received: 18 02 2022
pubmed: 9 12 2022
medline: 11 1 2023
entrez: 8 12 2022
Statut: ppublish

Résumé

The Notch pathway transmits signals between neighboring cells to elicit downstream transcriptional programs. Notch is a major regulator of cell fate specification, proliferation, and apoptosis, such that aberrant signaling leads to a pleiotropy of human diseases, including developmental disorders and cancers. The pathway signals through the transcription factor CSL (RBPJ in mammals), which forms an activation complex with the intracellular domain of the Notch receptor and the coactivator Mastermind. CSL can also function as a transcriptional repressor by forming complexes with one of several different corepressor proteins, such as FHL1 or SHARP in mammals and Hairless in Drosophila. Recently, we identified L3MBTL3 as a bona fide RBPJ-binding corepressor that recruits the repressive lysine demethylase LSD1/KDM1A to Notch target genes. Here, we define the RBPJ-interacting domain of L3MBTL3 and report the 2.06 Å crystal structure of the RBPJ-L3MBTL3-DNA complex. The structure reveals that L3MBTL3 interacts with RBPJ via an unusual binding motif compared to other RBPJ binding partners, which we comprehensively analyze with a series of structure-based mutants. We also show that these disruptive mutations affect RBPJ and L3MBTL3 function in cells, providing further insights into Notch mediated transcriptional regulation.

Identifiants

DOI: 10.1093/nar/gkac1137 PMID: 36477367 PMC: PMC9825171
pubmed: 36477367
pii: 6882124
doi: 10.1093/nar/gkac1137
pmc: PMC9825171
doi:

Substances chimiques

DNA-Binding Proteins 0
FHL1 protein, human 0
Histone Demethylases EC 1.14.11.-
Immunoglobulin J Recombination Signal Sequence-Binding Protein 0
Intracellular Signaling Peptides and Proteins 0
KDM1A protein, human EC 1.5.-
L3MBTL3 protein, human 0
LIM Domain Proteins 0
Muscle Proteins 0
RBPJ protein, human 0
Receptors, Notch 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

13083-13099

Subventions

Organisme : NIEHS NIH HHS
ID : T32 ES007250
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178974
Pays : United States

Informations de copyright

© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.

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Auteurs

Daniel Hall (D)

University of Cincinnati College of Medicine, Department of Molecular Genetics, Biochemistry and Microbiology, Cincinnati, OH, USA.

Benedetto Daniele Giaimo (BD)

Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.

Sung-Soo Park (SS)

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Wiebke Hemmer (W)

University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine 1, Albert-Einstein-Allee 23, 89081Ulm, Germany.

Tobias Friedrich (T)

Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.

Francesca Ferrante (F)

Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.

Marek Bartkuhn (M)

Biomedical Informatics and Systems Medicine, University of Giessen, 35392 Giessen, Germany.

Zhenyu Yuan (Z)

University of Cincinnati College of Medicine, Department of Molecular Genetics, Biochemistry and Microbiology, Cincinnati, OH, USA.

Franz Oswald (F)

University Medical Center Ulm, Center for Internal Medicine, Department of Internal Medicine 1, Albert-Einstein-Allee 23, 89081Ulm, Germany.
ORCID: 0000-0002-2923-5765

Tilman Borggrefe (T)

Institute of Biochemistry, University of Giessen, 35392 Giessen, Germany.
ORCID: 0000-0003-4325-5452

Jean-François Rual (JF)

Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
ORCID: 0000-0003-4465-8819

Rhett A Kovall (RA)

University of Cincinnati College of Medicine, Department of Molecular Genetics, Biochemistry and Microbiology, Cincinnati, OH, USA.
ORCID: 0000-0003-0520-1613

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › The structure, binding and function of a Notch...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The structure, binding and function of a Notch...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › The structure, binding and function of a Notch...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › The structure, binding and function of a Notch...
Recherchemedicale.com › Phénomènes génétiques › Régulation de l'expression des gènes › The structure, binding and function of a Notch...
Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Oxidoreductases › Oxidoreductases acting on CH-NH group donors › Oxidoreductases, (N-demethylating) › Histone Demethylases › The structure, binding and function of a Notch...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteur de transcription CBF-1 › The structure, binding and function of a Notch...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › The structure, binding and function of a Notch...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines à domaine LIM › The structure, binding and function of a Notch...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines contractiles › Protéines du muscle › The structure, binding and function of a Notch...
Recherchemedicale.com › Métabolisme › Liaison aux protéines › The structure, binding and function of a Notch...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Récepteurs Notch › The structure, binding and function of a Notch...