8wm9
Fzd4/DEP complex
Structural highlights
DiseaseFZD4_HUMAN Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry. FunctionFZD4_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Publication Abstract from PubMedWNT 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/beta-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. 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 Nat Commun. 2024 Sep 2;15(1):7644. doi: 10.1038/s41467-024-52174-z. PMID:39223191[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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