Structural Basis of Wnt Recognition by Frizzled

Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Science (Impact Factor: 33.61). 05/2012; 337(6090):59-64. DOI: 10.1126/science.1222879
Source: PubMed


Wnts are lipid-modified morphogens that play critical roles in development principally through engagement of Frizzled receptors. The 3.25 angstrom structure of Xenopus Wnt8 (XWnt8) in complex with mouse Frizzled-8 (Fz8) 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.

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    • "The seven-transmembrane Frizzled receptors (Fzds) were first demonstrated to function as Wnt receptors through direct binding and activation of downstream signaling (Bhanot et al., 1996; Janda et al., 2012). Fzd proteins, of which there are 10 family members in mammals, bind to Wnts through their large extracellular cysteine-rich domain (CRD), and have been shown to mediate both " canonical " and " noncanonical " Wnt signaling (Schulte, 2010; Mac- Donald and He, 2012; Niehrs, 2012). "
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    ABSTRACT: The morphology of the dendritic tree is critical to neuronal function and neural circuit wiring. Several Wnt family members have been demonstrated to play important roles in dendrite development. However, the Wnt receptors responsible for mediating this process remain largely elusive. Using primary hippocampal neuronal cultures as a model system, we report that Frizzled4 (Fzd4), a member of the Fzd family of Wnt receptors, specifically signals downstream of Wnt5a to promote dendrite branching and growth. Interestingly, the less conserved distal PDZ binding motif of Fzd4, and not its conserved proximal Dvl-interacting PDZ motif, is required for mediating this effect. We further showed that Dvl signaled parallel to and independent of Fzd4 in promoting dendrite growth. Unlike most previously described pathways, Wnt5a/Fzd4 signaling promoted dendrite development in an activity-independent and autocrine fashion. Together, these results provide the first identification of a Wnt receptor for regulating dendrite development in the mammalian system, and demonstrate a novel function of the distal PDZ motif of Fzd4 in dendrite morphogenesis, thereby expanding our knowledge of the complex roles of Wnt signaling in neural development. This article is protected by copyright. All rights reserved.
    Developmental Neurobiology 11/2014; 75(8). DOI:10.1002/dneu.22250 · 3.37 Impact Factor
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    • "It was shown previously that a mini-Wnt comprising the Xenopus Wnt8 CTD shows autonomous binding to Fz [9]. In addition, the inhibitory effects of Wnt NTDs have been reported in various studies [11-15]. "
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    ABSTRACT: Background Wnt proteins are a family of secreted signaling molecules that regulate key developmental processes in metazoans. The molecular basis of Wnt binding to Frizzled and LRP5/6 co-receptors has long been unknown due to the lack of structural data on Wnt ligands. Only recently, the crystal structure of the Wnt8-Frizzled8-cysteine-rich-domain (CRD) complex was solved, but the significance of interaction sites that influence Wnt signaling has not been assessed. Results Here, we present an extensive structure-function analysis of mouse Wnt3a in vitro and in vivo. We provide evidence for the essential role of serine 209, glycine 210 (site 1) and tryptophan 333 (site 2) in Fz binding. Importantly, we discovered that valine 337 in the site 2 binding loop is critical for signaling without contributing to binding. Mutations in the presumptive second CRD binding site (site 3) partly abolished Wnt binding. Intriguingly, most site 3 mutations increased Wnt signaling, probably by inhibiting Wnt-CRD oligomerization. In accordance, increasing amounts of soluble Frizzled8-CRD protein modulated Wnt3a signaling in a biphasic manner. Conclusions We propose a concentration-dependent switch in Wnt-CRD complex formation from an inactive aggregation state to an activated high mobility state as a possible modulatory mechanism in Wnt signaling gradients.
    BMC Biology 05/2014; 12(1):44. DOI:10.1186/1741-7007-12-44 · 7.98 Impact Factor
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    • "receptor (Janda et al., 2012) and its co-receptor, low-density lipoprotein receptor-related protein 6 (Lrp6) or the close relative Lrp5 (Figure 1A). The formation of a Wnt – Fzd– Lrp6 complex together with the recruitment of the scaffolding protein Dishevelled (Dvl) results in Lrp6 phosphorylation and activation and the recruitment of the Axin complex to the receptors. "
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    ABSTRACT: During the past three decades, the Wingless-type MMTV integration site (Wnt) signaling cascade has emerged as an essential system regulating multiple processes in developing and adult brain. Accumulating evidence points to a dysregulation of Wnt signaling in major neurodegenerative pathologies including Parkinson's disease (PD), a common neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic (mDA) neurons and deregulated activation of astrocyte and microglial. This review highlights the emerging link between Wnt signaling and key inflammatory pathways during mDA neuron damage/repair in PD progression. In particular, we summarize recent evidence documenting that aging and neurotoxicant exposure strongly antagonize Wnt/¦Â-catenin signaling in mDA neurons and subventricular zone (SVZ) neuroprogenitors via astrocyte-microglial interactions. Dysregulation of the crosstalk between Wnt/¦Â-catenin signaling and anti-oxidant/anti-inflammatory pathways delineate novel mechanisms driving the decline of SVZ plasticity with age and the limited nigrostrial dopaminergic self-repair in PD. These findings hold a promise in developing therapies that target Wnt/¦Â-catenin signaling to enhance endogenous restoration and neuronal outcome in age-dependent diseases, such as PD.
    Journal of Molecular Cell Biology 01/2014; 6(1). DOI:10.1093/jmcb/mjt053 · 6.77 Impact Factor
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