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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2024-09-02
DOI
https://doi.org/10.1038/s41467-024-52174-z
Citations
17
Primary Topic
Wnt/β-catenin signaling in development and cancer
Type
article
Field-Weighted Citation Impact
3.97

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Zhenmei Xu, Yangjie Xiong, Lu Yang, Yaning Duan et al.
17 citations
Nature Communications
Wnt/β-catenin signaling in development and cancer
3.97
article

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

Zhenmei Xu, Yangjie Xiong, Lu Yang, Yaning Duan, Fei Xu, Yuanzheng He, Lihua Jin, Jiyuan Ke, Xinyan Zhu, Zhengxiong Ma, Anqi Zhang, Jian Liu, Han Yin, Zhiwei Huang, Ruixue Xia, Woo Jae Kim, Changyou Guo, Qian Yu, Zongwei Zhang, Xinyu Tian, Jing Song
article en
17 citations

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.

Nature CommunicationsVol. 15(1)
Harbin Institute of Technology (CN), ShanghaiTech University (CN), Center for Life Sciences (CN), Northeast Forestry University (CN)
Westlake University, National Natural Science Foundation of China, Tsinghua University
Zero hunger
Openalex Percentile: Top 5%
Wnt/β-catenin signaling in development and cancer
3.97
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.