Title : Unsaturated fatty acyl recognition by
Frizzled receptors mediates
dimerization upon Wnt ligand binding
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