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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.

Original publication

DOI

10.1074/jbc.M112.428854

Type

Journal article

Journal

J Biol Chem

Publication Date

08/03/2013

Volume

288

Pages

7305 - 7312

Keywords

Amino Acid Sequence, Animals, Antibodies, Monoclonal, Blotting, Western, Calcium-Binding Proteins, Cell Line, Cell Line, Tumor, Drosophila Proteins, Flow Cytometry, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Ligands, Membrane Proteins, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Receptor, Notch1, Receptors, Notch, Sequence Homology, Amino Acid, Serrate-Jagged Proteins