Wnt Antagonists Bind through a Short Peptide to the First β-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, 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.