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Nat Struct Mol Biol. 2008 Aug;15(8):849-57. doi: 10.1038/nsmb.1457. Epub 2008 Jul 27.

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

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1
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

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.

PMID:
18660822
PMCID:
PMC2669539
DOI:
10.1038/nsmb.1457
[Indexed for MEDLINE]
Free PMC Article

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