Wnt Antagonists Bind through a Short Peptide to the First β-Propeller Domain of LRP5/6

被引：147

作者：

Bourhis, Eric ^{[1
]}

Wang, Weiru ^{[2
]}

Tam, Christine ^{[2
]}

Hwang, Jiyoung ^{[2
]}

Zhang, Yingnan ^{[1
]}

Spittler, Didier ^{[1
]}

Huang, Oscar W. ^{[1
]}

Gong, Yan ^{[4
]}

Estevez, Alberto ^{[2
]}

Zilberleyb, Inna ^{[2
]}

Rouge, Lionel ^{[2
]}

Chiu, Cecilia ^{[3
]}

Wu, Yan ^{[3
]}

Costa, Mike ^{[4
]}

Hannoush, Rami N. ^{[1
]}

Franke, Yvonne ^{[2
]}

Cochran, Andrea G. ^{[1
]}

机构：

[1] Genentech Res & Early Dev, Dept Early Discovery Biochem, San Francisco, CA 94080 USA

[2] Genentech Res & Early Dev, Dept Struct Biol, San Francisco, CA 94080 USA

[3] Genentech Res & Early Dev, Dept Antibody Engn, San Francisco, CA 94080 USA

[4] Genentech Res & Early Dev, Canc Targets, San Francisco, CA 94080 USA

来源：

STRUCTURE | 2011年 / 19卷 / 10期

基金：

加拿大健康研究院; 美国国家卫生研究院; 加拿大自然科学与工程研究理事会;

关键词：

HIGH-BONE-MASS; SECRETED PROTEIN; RECEPTOR; SCLEROSTIN; INHIBITION; MECHANISM; DICKKOPF-1; MUTATIONS; DENSITY; LIGAND;

D O I：

10.1016/j.str.2011.07.005

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 Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic targets in diseases involving bone loss or damage. It has been appreciated that Wnt coreceptors LRP5/6 are also important, as human missense mutations that result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to the El propeller domain of LRP5. Here, we report a crystal structure of LRP6 El bound to an antibody, revealing that the El domain is a peptide recognition module. Remarkably, the consensus El binding sequence is a close match to a conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We show that this motif is important for DKK1 and SOST binding to LRP6 and for inhibitory function, providing a detailed structural explanation for the effect of the BMD mutations.

引用

页码：1433 / 1442

页数：10

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