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Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Mar 08; Vol. 288 (10), pp. 7305-12. Date of Electronic Publication: 2013 Jan 21. - Publication Year :
- 2013
-
Abstract
- We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the development of paralogue-specific ligand-blocking antibodies. As a proof of principle, we have generated a Notch-1-specific monoclonal antibody that blocks binding, thus paving the way for antibody tools for research and therapeutic applications.
- Subjects :
- Amino Acid Sequence
Animals
Antibodies, Monoclonal immunology
Antibodies, Monoclonal pharmacology
Blotting, Western
Calcium-Binding Proteins genetics
Cell Line
Cell Line, Tumor
Drosophila Proteins chemistry
Drosophila Proteins genetics
Drosophila Proteins metabolism
Flow Cytometry
HEK293 Cells
Humans
Intercellular Signaling Peptides and Proteins genetics
Jagged-1 Protein
Ligands
Membrane Proteins genetics
Mice
Models, Molecular
Molecular Sequence Data
Mutation
Protein Binding drug effects
Protein Structure, Secondary
Protein Structure, Tertiary
Receptor, Notch1 genetics
Receptor, Notch1 immunology
Receptor, Notch1 metabolism
Receptors, Notch chemistry
Receptors, Notch genetics
Sequence Homology, Amino Acid
Serrate-Jagged Proteins
Calcium-Binding Proteins metabolism
Intercellular Signaling Peptides and Proteins metabolism
Membrane Proteins metabolism
Receptors, Notch metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23339193
- Full Text :
- https://doi.org/10.1074/jbc.M112.428854