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The Notch receptor and its ligands are key components in a core metazoan signaling pathway that regulates the spatial patterning, timing and outcome of many cell-fate decisions. Ligands contain a disulfide-rich Delta/Serrate/LAG-2 (DSL) domain required for Notch trans-activation or cis-inhibition. Here we report the X-ray structure of a receptor binding region of a Notch ligand, the DSL-EGF3 domains of human Jagged-1 (J-1(DSL-EGF3)). The structure reveals a highly conserved face of the DSL domain, and we show, by functional analysis of Drosophila melanogster ligand mutants, that this surface is required for both cis- and trans-regulatory interactions with Notch. We also identify, using NMR, a surface of Notch-1 involved in J-1(DSL-EGF3) binding. Our data imply that cis- and trans-regulation may occur through the formation of structurally distinct complexes that, unexpectedly, involve the same surfaces on both ligand and receptor.

Original publication

DOI

10.1038/nsmb.1457

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

08/2008

Volume

15

Pages

849 - 857

Keywords

Amino Acid Sequence, Animals, Calcium-Binding Proteins, Drosophila Proteins, Drosophila melanogaster, Gene Expression Regulation, Developmental, Humans, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Ligands, Magnetic Resonance Spectroscopy, Membrane Proteins, Molecular Sequence Data, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Receptor, Notch1, Sequence Homology, Amino Acid, Serrate-Jagged Proteins, Signal Transduction