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

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, mutatio...

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Bibliographic Details
Published in:Structure (London) 2011-10, Vol.19 (10), p.1433-1442
Main Authors: Bourhis, Eric, Wang, Weiru, Tam, Christine, Hwang, Jiyoung, Zhang, Yingnan, Spittler, Didier, Huang, Oscar W, Gong, Yan, Estevez, Alberto, Zilberleyb, Inna, Rouge, Lionel, Chiu, Cecilia, Wu, Yan, Costa, Mike, Hannoush, Rami N, Franke, Yvonne, Cochran, Andrea G
Format: Article
Language:English
Subjects:
Binding
Bones
Crystal structure
Density
Human
Inhibitors
Mutations
Peptides
Online Access:Get full text
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Summary: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 E1 propeller domain of LRP5. Here, we report a crystal structure of LRP6 E1 bound to an antibody, revealing that the E1 domain is a peptide recognition module. Remarkably, the consensus E1 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.
ISSN:0969-2126
DOI:10.1016/j.str.2011.07.005