8WMA

Fzd4/DEP complex (local refined)

Summary for 8WMA

• Entry DOI: 10.2210/pdb8wma/pdb
• EMDB information: 37647
• Descriptor: Frizzled-4, Segment polarity protein dishevelled homolog DVL-2 (2 entities in total)
• Functional Keywords: gpcr complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 139083.88

Authors

He, Y.,Qian, Y. (deposition date: 2023-10-03, release date: 2024-09-11, Last modification date: 2024-10-30)

Primary citation

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, W.J.,Ke, J.,Xu, F.,Huang, Z.,He, Y.
Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.
Nat Commun, 15:7644-7644, 2024

PubMed 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.

PubMed: 39223191
DOI: 10.1038/s41467-024-52174-z

Experimental method

ELECTRON MICROSCOPY (3.47 Å)