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Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains

Author

Listed:
  • Jinuk Kim

    (Seoul National University)

  • Wonhee Han

    (Pohang University of Science and Technology)

  • Taeyong Park

    (Seoul National University)

  • Eun Jin Kim

    (Seoul National University
    Plumbline Life Sciences, Inc.)

  • Injin Bang

    (Seoul National University
    Columbia University Irving Medical Center)

  • Hyun Sik Lee

    (Seoul National University)

  • Yejin Jeong

    (Sungkyunkwan University)

  • Kyeonghwan Roh

    (Seoul National University)

  • Jeesoo Kim

    (Seoul National University
    Center for RNA Research, Institute for Basic Science)

  • Jong-Seo Kim

    (Seoul National University
    Center for RNA Research, Institute for Basic Science)

  • 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)

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.

Suggested Citation

  • 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 & Hee-Jung Choi, 2020. "Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19155-4
    DOI: 10.1038/s41467-020-19155-4
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    Cited by:

    1. Timothy F. Shay & Seongmin Jang & Tyler J. Brittain & Xinhong Chen & Beth Walker & Claire Tebbutt & Yujie Fan & Damien A. Wolfe & Cynthia M. Arokiaraj & Erin E. Sullivan & Xiaozhe Ding & Ting-Yu Wang , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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