LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation

Area of Science:

• Cellular biology
• Molecular signaling
• Biochemistry

Background:

• Canonical Wnt/β-catenin signaling is crucial for development and disease.
• Current models propose Wnt, Frizzled (Frz), and LRP5/6 form a ternary complex for activation.
• Previous work indicated Frz and LRP5/6 interact pre-ligand binding, maintaining an inactive state.

Purpose of the Study:

• To investigate the structural changes and complex formation upon Wnt ligand stimulation.
• To elucidate the role of LRP6 dimerization in canonical Wnt pathway activation.

Main Methods:

• Biochemical assays to study protein interactions.
• Structural analysis of Wnt signaling complexes.
• Functional assays measuring canonical Wnt pathway activity.

Main Results:

• Wnt ligand stimulation induces a conformational change in the Frz-LRP6 complex.
• A hexameric complex (Wnt3a-Frz8-LRP6-LRP6-Frz8-Wnt3a) is formed, involving LRP6 homodimerization via its LDLR domain.
• LRP6 dimerization is critical for potent canonical Wnt pathway activation.

Conclusions:

• Canonical Wnt pathway activation involves a previously unrecognized mechanism.
• LRP6 homodimerization, mediated by the LDLR domain, is essential for signal initiation.
• This finding redefines the model of Wnt receptor complex formation and activation.