4f0a
Crystal structure of XWnt8 in complex with the cysteine-rich domain of Frizzled 8
Structural highlights
FunctionFZD8_MOUSE Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes (By similarity). The beta-catenin canonical 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. 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. Coreceptor along with RYK of Wnt proteins, such as WNT1.[1] [2] [3] [4] Publication Abstract from PubMedWnts are lipid-modified morphogens that play critical roles in development principally through engagement of Frizzled receptors. The 3.25 A structure of Xenopus Wnt8 (XWnt8) in complex with mouse Frizzled-8 cysteine-rich domain (CRD) reveals an unusual two-domain Wnt structure, not obviously related to known protein folds, resembling a "hand" with "thumb" and "index" fingers extended to grasp the Fz8-CRD at two distinct binding sites. One site is dominated by a palmitoleic acid lipid group projecting from Serine 187 at the tip of Wnt's thumb into a deep groove in the Fz8-CRD. In the second binding site, the conserved tip of Wnt's "index finger" forms hydrophobic amino acid contacts with a depression on the opposite side of the Fz8-CRD. The conservation of amino acids in both interfaces appears to facilitate ligand-receptor cross-reactivity, which has important implications for understanding Wnt's functional pleiotropy and for developing Wnt-based drugs for cancer and regenerative medicine. Structural Basis of Wnt Recognition by Frizzled.,Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC Science. 2012 May 31. PMID:22653731[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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