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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.

SUBMITTER: Cordle J 

PROVIDER: S-EPMC2669539 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.

Cordle Jemima J   Johnson Steven S   Tay Joyce Zi Yan JZ   Roversi Pietro P   Wilkin Marian B MB   de Madrid Beatriz Hernández BH   Shimizu Hideyuki H   Jensen Sacha S   Whiteman Pat P   Jin Boquan B   Redfield Christina C   Baron Martin M   Lea Susan M SM   Handford Penny A PA  

Nature structural & molecular biology 20080727 8


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 domai  ...[more]

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