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- Title
Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.
- Authors
Qian, Yu; Ma, Zhengxiong; Xu, Zhenmei; Duan, Yaning; Xiong, Yangjie; Xia, Ruixue; Zhu, Xinyan; Zhang, Zongwei; Tian, Xinyu; Yin, Han; Liu, Jian; Song, Jing; Lu, Yang; Zhang, Anqi; Guo, Changyou; Jin, Lihua; Kim, Woo Jae; Ke, Jiyuan; Xu, Fei; Huang, Zhiwei
- 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. Here the authors report the cryo-EM structure of Frizzeled 4 in complex with the DEP domain of Dishevelled 2. The study unveils the key mechanism of WNT signalling activation, the recruitment of dishevelled to Frizzled receptor.
- Subjects
WNT signal transduction; HOMEOSTASIS; MUTAGENESIS; DIMERIZATION; TRANSDUCERS
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-52174-z