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

• Published in: Nature communications Vol. 15; no. 1; pp. 7644 - 12
• Main 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, He, Yuanzheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52174-z

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.