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Wnt signalosome assembly by dep domain swapping of dishevelled

DOI: 10.1016/j.molcel.2016.08.026 DOI Help

Authors: Melissa V. Gammons (MRC Laboratory of Molecular Biology) , Miha Renko (MRC Laboratory of Molecular Biology) , Christopher M. Johnson (MRC Laboratory of Molecular Biology) , Trevor J. Rutherford (MRC Laboratory of Molecular Biology) , Mariann Bienz (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell , VOL 64 , PAGES 92 - 104

State: Published (Approved)
Published: October 2016
Diamond Proposal Number(s): 11235

Open Access Open Access

Abstract: 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.

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 23/11/2016 16:03


Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)