8j9n | pdb_00008j9n
Gq bound FZD1 in ligand-free state
Structural highlights
FunctionFZD1_HUMAN Receptor for Wnt proteins (PubMed:10557084). Activated by WNT3A, WNT3, WNT1 and to a lesser extent WNT2, but apparently not by WNT4, WNT5A, WNT5B, WNT6, WNT7A or WNT7B (PubMed:10557084). Contradictory results showing activation by WNT7B have been described for mouse (By similarity). Functions in the canonical Wnt/beta-catenin signaling pathway (PubMed:10557084). The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes (PubMed:10557084). 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 (Probable).[UniProtKB:O70421][1] (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium.[2] Publication Abstract from PubMedThe ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. Understanding FZD activation mechanism is key to unlock these emerging targets. Here we present the cryo-EM structures of FZD6 and FZD3 which are known to relay non-canonical planar cell polarity (PCP) signaling pathways as well as FZD1 in their G protein-coupled states and in the apo inactive states, respectively. Comparison of the three inactive/active pairs unveiled a shared activation framework among all ten FZDs. Mutagenesis along with imaging and functional analysis on the human lens epithelial tissues suggested potential crosstalk between the G-protein coupling of FZD6 and the PCP signaling pathways. Together, this study provides an integrated understanding of FZD structure and function, and lays the foundation for developing therapeutic modulators to activate or inhibit FZD signaling for a range of disorders including cancers and cataracts. A framework for Frizzled-G protein coupling and implications to the PCP signaling pathways.,Zhang Z, Lin X, Wei L, Wu Y, Xu L, Wu L, Wei X, Zhao S, Zhu X, Xu F Cell Discov. 2024 Jan 5;10(1):3. doi: 10.1038/s41421-023-00627-y. PMID:38182578[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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