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Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation

Author

Listed:
  • Yu Qian

    (Harbin Institute of Technology)

  • Zhengxiong Ma

    (Harbin Institute of Technology)

  • Zhenmei Xu

    (Harbin Institute of Technology)

  • Yaning Duan

    (Harbin Institute of Technology)

  • Yangjie Xiong

    (Harbin Institute of Technology)

  • Ruixue Xia

    (Harbin Institute of Technology)

  • Xinyan Zhu

    (Harbin Institute of Technology)

  • Zongwei Zhang

    (Harbin Institute of Technology)

  • Xinyu Tian

    (Harbin Institute of Technology)

  • Han Yin

    (Harbin Institute of Technology)

  • Jian Liu

    (Harbin Institute of Technology)

  • Jing Song

    (Harbin Institute of Technology)

  • Yang Lu

    (Harbin Institute of Technology)

  • Anqi Zhang

    (Harbin Institute of Technology)

  • Changyou Guo

    (Harbin Institute of Technology)

  • Lihua Jin

    (Northeast Forestry University)

  • Woo Jae Kim

    (Harbin Institute of Technology)

  • Jiyuan Ke

    (Hefei Comprehensive National Science Center)

  • Fei Xu

    (ShanghaiTech University)

  • Zhiwei Huang

    (Harbin Institute of Technology)

  • Yuanzheng He

    (Harbin Institute of Technology)

Abstract

WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.

Suggested Citation

  • Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52174-z
    DOI: 10.1038/s41467-024-52174-z
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