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Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains

Cited 59 time in Web of Science Cited 40 time in Scopus
Authors

Kim, Jinuk; Han, Wonhee; Park, Taeyong; Kim, Eun Jin; Bang, Injin; Lee, Hyun Sik; Jeong, Yejing; Roh, Kyeonghwan; Kim, Jeesoo; Kim, Jong-Seo; Kang, Chanhee; Seok, Chaok; Han, Jin-Kwan; Choi, Hee-Jung

Issue Date
2020-10
Publisher
Nature Publishing Group
Citation
Nature Communications, Vol.11 No.1, p. 5357
Abstract
Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the beta -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. The low-density lipoprotein receptor-related protein 6 (LRP6) is a co-receptor of the beta -catenin-dependent Wnt signaling pathway and interacts with the Wnt inhibitor sclerostin (SOST). Here the authors present the crystal structure of SOST in complex with the LRP6 E1E2 ectodomain construct, which reveals that the SOST C-terminus binds to the LRP6 E2 domain, and further validate this binding site with in vitro and in vivo experiments.
ISSN
2041-1723
URI
https://hdl.handle.net/10371/179955
DOI
https://doi.org/10.1038/s41467-020-19155-4
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  • College of Natural Sciences
  • School of Biological Sciences
Research Area Molecular Interactomics, Proteomics, Systems Biology, 단백체학, 분자상호작용체학, 시스템생물학

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