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Publication Abstract from PubMed

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 beta-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 beta-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.

Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled.,Gammons MV, Renko M, Johnson CM, Rutherford TJ, Bienz M Mol Cell. 2016 Oct 6;64(1):92-104. doi: 10.1016/j.molcel.2016.08.026. Epub 2016, Sep 29. PMID:27692984^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.