title: A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Jemima
authors.initials: J
authors.lastname: Cordle
authors.forename: Steven
authors.initials: S
authors.lastname: Johnson
authors.forename: Joyce Zi Yan
authors.initials: JZ
authors.lastname: Tay
authors.forename: Pietro
authors.initials: P
authors.lastname: Roversi
authors.forename: Marian B
authors.initials: MB
authors.lastname: Wilkin
authors.forename: Beatriz Hernández
authors.initials: BH
authors.lastname: de Madrid
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Sacha
authors.initials: S
authors.lastname: Jensen
authors.forename: Pat
authors.initials: P
authors.lastname: Whiteman
authors.forename: Boquan
authors.initials: B
authors.lastname: Jin
authors.forename: Christina
authors.initials: C
authors.lastname: Redfield
authors.forename: Martin
authors.initials: M
authors.lastname: Baron
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lea
authors.forename: Penny A
authors.initials: PA
authors.lastname: Handford
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
chemical_list: D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins