Structural highlights
Disease
FZD6_HUMAN Autosomal recessive nail dysplasia. The disease is caused by variants affecting the gene represented in this entry. Rare non-synonymous variants in FZD6 may contribute to neural tube defects, congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy.
Function
C562_ECOLX Electron-transport protein of unknown function.FZD6_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. 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. Together with FZD3, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear (By similarity).[UniProtKB:Q61089]
Publication Abstract from PubMed
The 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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhang Z, Lin X, Wei L, Wu Y, Xu L, Wu L, Wei X, Zhao S, Zhu X, Xu F. A framework for Frizzled-G protein coupling and implications to the PCP signaling pathways. Cell Discov. 2024 Jan 5;10(1):3. PMID:38182578 doi:10.1038/s41421-023-00627-y
