title: Autoinhibition of Dishevelled protein regulated by its extreme C terminus plays a distinct role in Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling pathways.
abstract: Dishevelled (Dvl) is a key intracellular signaling molecule that mediates the activation of divergent Wnt pathways. It contains three highly conserved domains known as DIX, PDZ, and DEP, the functions of which have been well characterized in β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt signaling. The C-terminal region is also highly conserved from invertebrates to vertebrates. However, its function in regulating the activation of different Wnt signals remains unclear. We reported previously that Dvl conformational change triggered by the highly conserved PDZ-binding C terminus is important for the pathway specificity. Here we provide further evidence demonstrating that binding of the C terminus to the PDZ domain results in Dvl autoinhibition in the Wnt signaling pathways. Therefore, the forced binding of the C terminus to the PDZ domain reduces the activity of Dvl in noncanonical Wnt signaling, whereas obstruction of this interaction releases Dvl autoinhibition, impairs its functional interaction with LRP6 in canonical Wnt signaling, and increases its specificity in noncanonical Wnt signaling, which is closely correlated with an enhanced Dvl membrane localization. Our findings highlight the importance of the C terminus in keeping Dvl in an appropriate autoinhibited state, accessible for regulation by other partners to switch pathway specificity. Particularly, the C-terminally tagged Dvl fusion proteins that have been widely used to study the function and cellular localization of Dvl may not truly represent the wild-type Dvl because those proteins cannot be autoinhibited.
authors.affiliation: From the School of Life Sciences, Shandong University, 27 Shanda Nan Road, Jinan 250100, China.|the Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan 250100, China, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.affiliation: the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: the Institut de Biologie Paris-Seine (IBPS)-Developmental Biology Laboratory, Sorbonne Universités-Université Pierre et Marie Curie (UPMC), University of Paris 06, CNRS UMR7622, 75005 Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Saquet
authors.affiliation: From the School of Life Sciences, Shandong University, 27 Shanda Nan Road, Jinan 250100, China.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Cheng
authors.affiliation: From the School of Life Sciences, Shandong University, 27 Shanda Nan Road, Jinan 250100, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shao
authors.affiliation: the Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, jzheng@jsei.ucla.edu.|the Stein Eye Institute, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095.|the Molecular Biology Institute, UCLA, Los Angeles, California 90095.
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: From the School of Life Sciences, Shandong University, 27 Shanda Nan Road, Jinan 250100, China, de-li.shi@upmc.fr.|the Institut de Biologie Paris-Seine (IBPS)-Developmental Biology Laboratory, Sorbonne Universités-Université Pierre et Marie Curie (UPMC), University of Paris 06, CNRS UMR7622, 75005 Paris, France.
authors.forename: De-Li
authors.initials: DL
authors.lastname: Shi
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity / Q000502:physiology*; D000072261:Dishevelled Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000072417:Protein Domains; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072261:Dishevelled Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
keywords: PDZ domain; Wnt pathway; Wnt signaling; signal transduction; structural biology