Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains

Jinuk Kim, Wonhee Han, Taeyong Park, Eun Jin Kim, Injin Bang, Hyun Sik Lee, Yejin Jeong, Kyeonghwan Roh, Jeesoo Kim, Jong-Seo Kim, Chanhee Kang, Chaok Seok, Jin-Kwan Han and Hee-Jung Choi ()
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Jinuk Kim: Seoul National University
Wonhee Han: Pohang University of Science and Technology
Taeyong Park: Seoul National University
Eun Jin Kim: Seoul National University
Injin Bang: Seoul National University
Hyun Sik Lee: Seoul National University
Yejin Jeong: Sungkyunkwan University
Kyeonghwan Roh: Seoul National University
Jeesoo Kim: Seoul National University
Jong-Seo Kim: Seoul National University
Chanhee Kang: Seoul National University
Chaok Seok: Seoul National University
Jin-Kwan Han: Pohang University of Science and Technology
Hee-Jung Choi: Seoul National University

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2–SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling.

Date: 2020
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DOI: 10.1038/s41467-020-19155-4

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