Inhibition of Wnt signaling by Dishevelled PDZ peptides

Zhang, Yingnan; Appleton, B.A.; Wiesmann, Christian; Lau, Ted; Costa, Mike; Hannoush, Rami N.; Sidhu, Sachdev S.

doi:10.1038/nchembio.152

Cited by 147 publications

(171 citation statements)

References 17 publications

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“…A thorough understanding of the mechanism of Fz-Dvl complex formation is crucial to clarify how downstream signaling events are controlled. Moreover, Fz-Dvl interactions provide an attractive target for the design and development of drugs that interfere with Wnt signaling activation (24,(41)(42)(43). Although the Dvl PDZ domain was shown to bind an Fz C-terminal tailderived peptide in vitro (9,23), evidence for in vivo binding of the Dvl PDZ domain to Fz remains scarce.…”

Section: Discussionmentioning

confidence: 99%

“…The relative low affinity of this interaction suggested the need for additional molecular interactions in the formation of a stable Fz-Dvl complex in vivo in cells. Moreover, the binding cleft of Dvl PDZ appears highly flexible and accommodates binding of a diverse set of peptide ligands in vitro as well as numerous Dvl PDZ binding partners in cells (24)(25)(26). How these interactors compete for Dvl PDZ domain binding and how specificity is achieved during Wnt signaling remain unresolved.…”

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confidence: 99%

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Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Tauriello

Jordens

Kirchner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

190

218

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Wnt binding to members of the seven-span transmembrane Frizzled (Fz) receptor family controls essential cell fate decisions and tissue polarity during development and in adulthood. The Fzmediated membrane recruitment of the cytoplasmic effector Dishevelled (Dvl) is a critical step in Wnt/β-catenin signaling initiation, but how Fz and Dvl act together to drive downstream signaling events remains largely undefined. Here, we use an Fz peptide-based microarray to uncover a mechanistically important role of the bipartite Dvl DEP domain and C terminal region (DEP-C) in binding a three-segmented discontinuous motif in Fz. We show that cooperative use of two conserved motifs in the third intracellular loop and the classic C-terminal motif of Fz is required for DEP-C binding and Wnt-induced β-catenin activation in cultured cells and Xenopus embryos. Within the complex, the Dvl DEP domain mainly binds the Fz C-terminal tail, whereas a short region at the Dvl C-terminal end is required to bind the Fz third loop and stabilize the Fz-Dvl interaction. We conclude that Dvl DEP-C binding to Fz is a key event in Wnt-mediated signaling relay to β-catenin. The discontinuous nature of the Fz-Dvl interface may allow for precise regulation of the interaction in the control of Wnt-dependent cellular responses.peptide microarray | protein-protein interaction | Wingless signaling

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Tauriello

Jordens

Kirchner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

190

218

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“…Dimerization and vesicle localization have been ascribed to the DIX domain and plasma membrane localization to the DEP domain (24,25). The PDZ domain of Dvl has greater flexibility in target binding than conventional PDZ domains, which bind type 1 and 2 targets at the C termini of transmembrane proteins (26). In addition to binding a wider range of C-terminal targets, the PDZ domain of Dvl-2 recognizes an internal motif within Frizzled.…”

Section: Discussionmentioning

confidence: 99%

Myristoylated Naked2 Antagonizes Wnt-β-Catenin Activity by Degrading Dishevelled-1 at the Plasma Membrane

Cao

et al. 2010

Journal of Biological Chemistry

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In Drosophila, naked cuticle is an inducible antagonist of the Wnt-␤-catenin pathway, likely acting at the level of Dishevelled (Dsh/Dvl), an essential component of this pathway. The mechanism by which naked cuticle and its two vertebrate orthologs, Naked1 (NKD1) and Naked2 (NKD2), inhibit Dvl function is unknown. NKD2 is myristoylated, a co-translational modification that leads to its plasma membrane localization. In contrast, myristoylation-deficient G2A NKD2 is cytoplasmic. Herein we show that the ability of Nkd2/NKD2 to antagonize Wnt-␤-catenin activity during zebrafish embryonic development and in mammalian HEK293 cells is myristoylation-dependent. NKD2 and Dvl-1 interact and co-localize at the lateral membrane of polarized epithelial cells. In reciprocal overexpression and siRNA knockdown experiments, NKD2 and Dvl-1 destabilize each other via enhanced polyubiquitylation; this effect is also dependent upon Naked2 myristoylation. Cell fractionation and ubiquitylation assays indicate that endogenous NKD2 interacts with a slower migrating, ubiquitylated form of Dvl-1 in plasma membrane fractions. These results provide a mechanism by which NKD2 antagonizes Wnt signaling: myristoylated NKD2 interacts with Dvl-1 at the plasma membrane, and this interaction leads to their mutual ubiquitin-mediated proteasomal degradation.

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“…For instance, the recent structure of Dvl2 PDZ domain in complex with a noncanonical C-terminal sequence (WKWYGWF) revealed a conformation of the glycine residue at P(-2), which allowed the P(-3) tyrosine residue to occupy the binding position occupied by a P(-2) residue in the canonical arrangement. 8 We have previously shown that addition of appropriate C-terminal extensions to constructs of PDZ domains greatly assists in the formation of PDZ domain crystals, with each PDZ domain binding the C-terminus of a crystallographically adjacent molecule. 9 The C-terminal extensions can be chosen either based on the sequence of a known binding target of the PDZ domain or based on a likely target sequence according to the class of the PDZ domain.…”

Section: Introductionmentioning

confidence: 99%

Unusual binding interactions in PDZ domain crystal structures help explain binding mechanisms

et al. 2010

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PDZ domains most commonly bind the C-terminus of their protein targets. Typically the C-terminal four residues of the protein target are considered as the binding motif, particularly the C-terminal residue (P0) and third-last residue (P-2) that form the major contacts with the PDZ domain's ''binding groove''. We solved crystal structures of seven human PDZ domains, including five of the seven PDLIM family members. The structures of GRASP, PDLIM2, PDLIM5, and PDLIM7 show a binding mode with only the C-terminal P0 residue bound in the binding groove. Importantly, in some cases, the P-2 residue formed interactions outside of the binding groove, providing insight into the influence of residues remote from the binding groove on selectivity. In the GRASP structure, we observed both canonical and noncanonical binding in the two molecules present in the asymmetric unit making a direct comparison of these binding modes possible. In addition, structures of the PDZ domains from PDLIM1 and PDLIM4 also presented here allow comparison with canonical binding for the PDLIM PDZ domain family. Although influenced by crystal packing arrangements, the structures nevertheless show that changes in the positions of PDZ domain side-chains and the aB helix allow noncanonical binding interactions.

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Inhibition of Wnt signaling by Dishevelled PDZ peptides

Cited by 147 publications

References 17 publications

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Myristoylated Naked2 Antagonizes Wnt-β-Catenin Activity by Degrading Dishevelled-1 at the Plasma Membrane

Unusual binding interactions in PDZ domain crystal structures help explain binding mechanisms

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