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

被引：200

作者：

Cordle, Jemima ^{[1
]}

Johnson, Steven ^{[2
]}

Tay, Joyce Zi Yan ^{[1
,2
]}

Roversi, Pietro ^{[2
]}

Wilkin, Marian B. ^{[3
]}

de Madrid, Beatriz Hernandez ^{[3
]}

Shimizu, Hideyuki ^{[3
]}

Jensen, Sacha ^{[1
]}

Whiteman, Pat

Jin, Boquan ^{[4
]}

Redfield, Christina ^{[1
]}

Baron, Martin ^{[3
]}

Lea, Susan M. ^{[2
]}

Handford, Penny A. ^{[1
]}

机构：

[1] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England

[2] Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England

[3] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England

[4] Fourth Mil Med Univ, Dept Immunol, Xian 710032, Shaanxi, Peoples R China

来源：

NATURE STRUCTURAL & MOLECULAR BIOLOGY | 2008年 / 15卷 / 08期

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1038/nsmb.1457

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：849 / 857

页数：9

共 54 条

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