Structural Basis of Wnt Recognition by Frizzled

By C. Y. Janda, D. Waghray, Aron M. Levin, C. Thomas, K. Garcia. 2012

858 citations recorded by the source corpus.

Dissecting Wnt/Fz Interaction Wnt proteins activate the transmembrane receptor Frizzled (Fz) to initiate pathways central to vertebrate and invertebrate development. Wnts are palmitoylated, which has complicated structural and functional characterization. Janda et al. (p. 59, published online 31 May; see the Perspective by Bienz and He) achieved coexpression and purification of Xenopus Wnt8 (XWnt8) with mouse Fz8 cysteine rich domain (CRD) and determined a crystal structure of the complex. Wnt binds to the Fz8 CRD at two distinct sites with the lipid group playing a key role in the first interface. Both interfaces involve conserved amino acids, which may explain the known pleiotropy of the Wnt/Fz interaction. The structure of the morphogen Wnt bound to its receptor provides a basis for understanding Wnt’s functional pleiotropy. 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.

Subfields: Molecular Biology

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In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. M. Resh
4. Jessica Rios-Esteves
5. S. Angers
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7. G. Schulte
8. J. Petersen

Citations in the corpus

• Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, neutral): “Consistent with this mode of transfer, we note that the conformation of WNT8A used here was essentially unchanged from its conformation bound to WLS (Nygaard et al., 2021), and that WNT3 in its FZD CRD bound conformation (PDB 6AHY) could not dock to PORCN in a reasonable position (Hirai et al., 2019”
• Notum is required for neural and head induction via Wnt deacylation, oxidation and inactivation (2015, neutral): “Mass spectrometry of Wnt3a and the Wnt8 crystal structure suggest that O-palmitoleoylation and N-glycosylation are the predominant modifications of an active Wnt protein (Janda et al., 2012; Takada et al., 2006; Zhang et al., 2012).”
• An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control (2014, background): “Once delivered to their target cells, Wnt ligands engage their cognate Frizzled receptors through their palmitate group, which extends into the lipid-binding cysteine-rich domain (CRD) of Frizzled receptors (6).”
• Precise Regulation of Porcupine Activity Is Required for Physiological Wnt Signaling (2012, background): “In addition, palmitoylation is essential for the ability of Wnts to interact with Frizzled receptors at the cell surface (19–21).”
• Wnt/β-catenin signaling and disease. (2012, positive): “Most recently, the structure of the Xenopus Wnt8 protein as bound to Frizzled was solved, revealing two domains on Wnt that interact with the receptor (Janda et al., 2012).”
• An in vitro fatty acylation assay reveals a mechanism for Wnt recognition by the acyltransferase Porcupine (2017, background): “In the three-dimensional crystal structure of Xenopus Wnt8, the acylated serine is located at the base of a loop whose structure is constrained by two sets of disulfide-bonded cysteines (4).”
• Structural basis of WLS/Evi-mediated Wnt transport and secretion (2020, background): “An intriguing change that occurs when Wnt moves from WLS to the FZD CRD is the conformational change of the highly conserved hairpin 3 (Figure 4B) that is proposed to be the major determinant of FZD binding affinity (Janda et al., 2012).”
• Wnt signaling in development and tissue homeostasis (2018, background): “Structural studies have revealed that Wnt proteins resemble the general structure of a hand, with the thumb and index fingers pinching the extracellular CRD of Frizzled.”
• In vitro reconstitution of Wnt acylation reveals structural determinants of substrate recognition by the acyltransferase human Porcupine (2018, background): “The structure of XWnt8 bound to the cysteine-rich domain of mouse Frizzled-8 showed that the site of palmitoleoylation has a tongue-shaped structure that is held together by multiple disulfide bonds (5).”