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.

1. Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
2. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
3. Faculty of Life Sciences, Michael Smith Building, University of Manchester, Stopford Road, Manchester M13 9PT, UK.
4. Department of Immunology, Fourth Military Medical University, 17 West Changle Road, Xi'an, Shaanxi 710032, PR China.
5. These authors contributed equally to this work.

Correspondence to: Penny A Handford¹ e-mail: penny.handford@bioch.ox.ac.uk

Correspondence to: Susan M Lea² e-mail: susan.lea@path.ox.ac.uk

Correspondence to: Martin Baron³ e-mail: martin.baron@manchester.ac.uk

Correspondence to: Christina Redfield¹ e-mail: christina.redfield@bioch.ox.ac.uk

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