5SUY

Domain-swapped dimer of human Dishevelled2 DEP domain: monoclinic crystal form crystallised from dimeric fraction

Summary for 5SUY

• Entry DOI: 10.2210/pdb5suy/pdb
• Descriptor: Segment polarity protein dishevelled homolog DVL-2, SULFATE ION (3 entities in total)
• Functional Keywords: dishevelled, dep domain, wnt signalling, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Peripheral membrane protein ; Cytoplasmic side : O14641
• Total number of polymer chains: 4
• Total formula weight: 43673.63

Authors

Renko, M.,Gammons, M.V.,Bienz, M. (deposition date: 2016-08-04, release date: 2016-10-12, Last modification date: 2024-05-01)

Primary citation

Gammons, M.V.,Renko, M.,Johnson, C.M.,Rutherford, T.J.,Bienz, M.
Wnt Signalosome Assembly by DEP Domain Swapping of Dishevelled.
Mol.Cell, 64:92-104, 2016

PubMed 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.

PubMed: 27692984
DOI: 10.1016/j.molcel.2016.08.026

Experimental method

X-RAY DIFFRACTION (1.88 Å)