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

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 Jin, Woo Jae Kim, Jiyuan Ke, Fei Xu, Zhiwei Huang and Yuanzheng He ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52174-z

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