한빛사논문
Jinuk Kim1, Wonhee Han2, Taeyong Park3, Eun Jin Kim1,6, Injin Bang1,7, Hyun Sik Lee1, Yejing Jeong4, Kyeonghwan Roh1, Jeesoo Kim1,5, Jong-Seo Kim1,5, Chanhee Kang1, Chaok Seok3, Jin-Kwan Han2 & Hee-Jung Choi1,*
1Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
2Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 37673, Republic of Korea.
3Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea. 4School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
5Center for RNA Research, Institute for Basic Science, Seoul 08826, Republic of Korea. 6Present address: Plumbline Life Sciences, Inc., Seoul 06552, Republic of Korea.
7Present address: Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA.
*Corresponding author
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.
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TOP52020년 후보
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