Structural basis of Wnt recognition by Frizzled.
Wnts are lipid-modified morphogens that play critical roles in development principally through engagement of Frizzled receptors. The 3.25 angstrom structure of Xenopus Wnt8 (XWnt8) in complex with mouse Frizzled-8 (Fz8) cysteine-rich domain (CRD) reveals an unusual two-domain Wnt structure, not obviously related to known protein folds, resembling a "hand" with "thumb" and "index" fingers extended to grasp the Fz8-CRD at two distinct binding sites. One site is dominated by a palmitoleic acid lipid group projecting from serine 187 at the tip of Wnt''s thumb into a deep groove in the Fz8-CRD. In the second binding site, the conserved tip of Wnt''s "index finger" forms hydrophobic amino acid contacts with a depression on the opposite side of the Fz8-CRD. The conservation of amino acids in both interfaces appears to facilitate ligand-receptor cross-reactivity, which has important implications for understanding Wnt''s functional pleiotropy and for developing Wnt-based drugs for cancer and regenerative medicine.
PubMed ID: 22653731
PMC ID: PMC3577348
Article link: Science.
Grant support: R01-GM097015 NIGMS NIH HHS , Howard Hughes Medical Institute , R01 GM097015 NIGMS NIH HHS
Genes referenced: fzd8 wnt8a