Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled
| Autor: | Christopher M. Johnson, Trevor J. Rutherford, Melissa V. Gammons, Miha Renko, Mariann Bienz |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Protein Conformation alpha-Helical Frizzled Wnt signalosome Amino Acid Motifs Dishevelled Proteins Gene Expression Biology Article Wnt signalosome assembly 03 medical and health sciences Protein structure Chlorocebus aethiops Escherichia coli Animals Humans Protein Interaction Domains and Motifs Cloning Molecular Molecular Biology beta Catenin chemistry.chemical_classification Binding Sites Wnt signaling pathway Cell Biology Frizzled Receptors Dishevelled Cell biology Wnt Proteins 030104 developmental biology HEK293 Cells chemistry Gene Expression Regulation DEP domain COS Cells Protein Conformation beta-Strand Signal transduction Protein Multimerization HeLa Cells Protein Binding Signal Transduction |
| Zdroj: | Molecular Cell |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2016.08.026 |
| Popis: | Summary Extracellular signals are often transduced by dynamic signaling complexes (“signalosomes”) assembled by oligomerizing hub proteins following their recruitment to signal-activated transmembrane receptors. A paradigm is the Wnt signalosome, which is assembled by Dishevelled via reversible head-to-tail polymerization by its DIX domain. Its activity causes stabilization of β-catenin, a Wnt effector with pivotal roles in animal development and cancer. How Wnt triggers signalosome assembly is unknown. Here, we use structural analysis, as well as biophysical and cell-based assays, to show that the DEP domain of Dishevelled undergoes a conformational switch, from monomeric to swapped dimer, to trigger DIX-dependent polymerization and signaling to β-catenin. This occurs in two steps: binding of monomeric DEP to Frizzled followed by DEP domain swapping triggered by its high local concentration upon Wnt-induced recruitment into clathrin-coated pits. DEP domain swapping confers directional bias on signaling, and the dimerization provides cross-linking between Dishevelled polymers, illustrating a key principle underlying signalosome formation. Graphical Abstract Image 1 Highlights • Wnt signalosome assembly by Dishevelled depends on DEP-dependent dimerization • DEP dimerization via domain swapping favors unidirectional signaling • DEP-dependent cross-linking of Dishevelled polymers triggers phase transition • DEP dimerization is mutually exclusive with DEP-dependent binding to Frizzled Gammons et al. discover that Wnt signalosome formation by Dishevelled depends on dimerization by its DEP domain via domain swapping. This cross-links DIX-dependent Dishevelled polymers and, thus, promotes phase transition. They propose that DEP domain swapping triggered by high local concentration of Dishevelled in clathrin-coated pits initiates Wnt signal transduction. |
| Databáze: | OpenAIRE |
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