Structural basis of Wnt recognition by Frizzled

Area of Science:

• Molecular Biology
• Developmental Biology
• Structural Biology

Background:

• Wnt proteins are crucial lipid-modified morphogens directing development via Frizzled receptor interactions.
• Understanding Wnt-Frizzled complex structure is key to deciphering developmental signaling pathways.

Purpose of the Study:

• To elucidate the structural basis of Xenopus Wnt8 (XWnt8) interaction with the mouse Frizzled-8 cysteine-rich domain (Fz8-CRD).
• To investigate the role of lipid modification and conserved residues in Wnt-Frizzled binding and cross-reactivity.

Main Methods:

• X-ray crystallography was used to determine the 3.25 angstrom structure of the XWnt8-Fz8-CRD complex.
• Analysis of protein-ligand interfaces, including lipid and amino acid interactions, was performed.

Main Results:

• The study revealed an unusual two-domain Wnt structure, resembling a 'hand' with distinct binding sites for Fz8-CRD.
• A palmitoleic acid lipid group at the Wnt 'thumb' tip binds to a deep groove in Fz8-CRD.
• Hydrophobic contacts between Wnt 'index' finger and Fz8-CRD were identified, involving conserved amino acids.

Conclusions:

• The conserved interfaces and lipid interaction explain Wnt-Frizzled cross-reactivity and functional pleiotropy.
• These findings have significant implications for developing targeted Wnt-based therapeutics for cancer and regenerative medicine.