Journal Article

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

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

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/45/612/194 / 631/535/1258/1259 / 631/80/86/2363 / 82/16 / 82/83 / Arrestin / Cryoelectron Microscopy / Dimerization / Dishevelled protein / Dishevelled Proteins - chemistry / Dishevelled Proteins - genetics / Dishevelled Proteins - metabolism / Frizzled protein / Frizzled Receptors - chemistry / Frizzled Receptors - genetics / Frizzled Receptors - metabolism / G protein-coupled receptors / HEK293 Cells / Homeostasis / Humanities and Social Sciences / Humans / Hydrophobicity / Inserts / Models, Molecular / Molecular structure / multidisciplinary / Mutagenesis / Protein Binding / Protein Domains / Protein structure / Receptors / Science / Science (multidisciplinary) / Signal transduction / Wnt protein / Wnt Signaling Pathway