EMD-37647

Single-particle
3.47 Å
EMD-37647 Deposition: 03/10/2023
Map released: 11/09/2024
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-37647

Fzd4/DEP complex (local refined)

EMD-37647

Single-particle
3.47 Å
EMD-37647 Deposition: 03/10/2023
Map released: 11/09/2024
Last modified: 30/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens
Sample: GPCR complex
Fitted models: 8wma

Deposition Authors: He Y , Qian Y
Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.
Qian Y, Ma Z, Xu Z, Duan Y, Xiong Y, Xia R, Zhu X, Zhang Z, Tian X, Yin H, Liu J, Song J, Lu Y, Zhang A, Guo C, Jin L, Kim WJ , Ke J, Xu F , Huang Z , He Y
(2024) Nat Commun , 15 , 7644 - 7644
PUBMED: 39223191
DOI: doi:10.1038/s41467-024-52174-z
ISSN: 2041-1723
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.