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Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding
Aaron H Nile1, Susmith Mukund2, Karen Stanger1
1Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA 94080.
Abstract:
Frizzled (FZD) receptors mediate Wnt signaling in diverse processes ranging from bone growth to stem cell activity. Moreover, high FZD receptor expression at the cell surface contributes to overactive Wnt signaling in subsets of pancreatic, ovarian, gastric, and colorectal tumors. Despite the progress in biochemical understanding of Wnt-FZD receptor interactions, the molecular basis for recognition of Wnt cis-unsaturated fatty acyl groups by the cysteine-rich domain (CRD) of FZD receptors remains elusive. Here, we determined a crystal structure of human FZD7 CRD unexpectedly bound to a 24-carbon fatty acid. We also report a crystal structure of human FZD5 CRD bound to C16:1 cis-Δ9 unsaturated fatty acid. Both structures reveal a dimeric arrangement of the CRD. The lipid-binding groove exhibits flexibility and spans both monomers, adopting a U-shaped geometry that accommodates the fatty acid. Re-evaluation of the published mouse FZD8 CRD structure reveals that it also shares the same architecture as FZD5 and FZD7 CRDs. Our results define a common molecular mechanism for recognition of the cis-unsaturated fatty acyl group, a necessary posttranslational modification of Wnts, by multiple FZD receptors. The fatty acid bridges two CRD monomers, implying that Wnt binding mediates FZD receptor dimerization. Our data uncover possibilities for the arrangement of Wnt-FZD CRD complexes and shed structural insights that could aide in the identification of pharmacological strategies to modulate FZD receptor function.
Insights
Structural insights reveal how Frizzled (FZD) receptors recognize Wnt proteins. Fatty acids bind to FZD cysteine-rich domains (CRDs), bridging two CRDs and suggesting Wnt binding induces receptor dimerization.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Frizzled (FZD) receptors are crucial mediators of Wnt signaling, impacting processes like bone growth and stem cell activity.
- Overexpressed FZD receptors are implicated in various cancers, including pancreatic, ovarian, gastric, and colorectal tumors.
- The precise molecular mechanism by which FZD receptors recognize the unsaturated fatty acyl modifications of Wnt proteins remains unclear.
Purpose of the Study:
- To elucidate the structural basis of Wnt-FZD receptor interaction, specifically focusing on the recognition of cis-unsaturated fatty acyl groups by the FZD cysteine-rich domain (CRD).
- To investigate the potential for FZD receptor dimerization upon Wnt binding.
Main Methods:
- Determined crystal structures of human FZD7 CRD bound to a 24-carbon fatty acid.
- Determined crystal structures of human FZD5 CRD bound to a C16:1 cis-Δ9 unsaturated fatty acid.
- Re-analyzed the published crystal structure of mouse FZD8 CRD.
Main Results:
- The crystal structures revealed a conserved dimeric arrangement of FZD CRDs.
- A flexible, U-shaped lipid-binding groove spanning both CRD monomers was identified, accommodating the bound fatty acid.
- FZD5, FZD7, and FZD8 CRDs share a common architecture for fatty acid recognition.
- The fatty acid acts as a bridge between two CRD monomers, suggesting Wnt binding induces FZD receptor dimerization.
Conclusions:
- A common molecular mechanism for the recognition of cis-unsaturated fatty acyl groups by multiple FZD receptors has been defined.
- The findings suggest that Wnt binding promotes FZD receptor dimerization through CRD interactions.
- These structural insights provide a foundation for developing strategies to modulate FZD receptor function pharmacologically.