Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled.

Melissa V Gammons, Miha Renko, Christopher M Johnson, Trevor J Rutherford, Mariann Bienz

Molecular cell 2016 Oct 06

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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. Copyright © 2016 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.

Citation

Melissa V Gammons, Miha Renko, Christopher M Johnson, Trevor J Rutherford, Mariann Bienz. Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled. Molecular cell. 2016 Oct 06;64(1):92-104