Structural Basis of Wnt Recognition by Frizzled

TLDR

Wnts are lipid‑modified morphogens essential for development, acting mainly by binding Frizzled receptors. The 3.25‑Å crystal structure of Xenopus Wnt8 bound to mouse Frizzled‑8 CRD reveals a hand‑shaped Wnt that engages the receptor at two sites—palmitoleic acid from serine 187 inserts into a deep groove and the index finger contacts a hydrophobic pocket—conserved residues at both interfaces suggest cross‑reactivity, informing Wnt pleiotropy and therapeutic design.

Abstract

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.