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Structure. 2011 Oct 12;19(10):1433-42. doi: 10.1016/j.str.2011.07.005. Epub 2011 Sep 22.

Wnt antagonists bind through a short peptide to the first β-propeller domain of LRP5/6.

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1
Department of Early Discovery Biochemistry, Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.

Abstract

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.

PMID:
21944579
DOI:
10.1016/j.str.2011.07.005
[Indexed for MEDLINE]
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