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.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Claudia Y
CY
Janda
Deepa
D
Waghray
Aron M
AM
Levin
Christoph
C
Thomas
K Christopher
KC
Garcia
D000215:Acylation; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D006031:Glycosylation; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D051153:Wnt Proteins / Q000737:chemistry* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D029867:Xenopus Proteins / Q000737:chemistry* / Q000378:metabolism; D014982:Xenopus laevis
D003545:Cysteine; D005229:Fatty Acids, Monounsaturated; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; C511610:Fzd8 protein, mouse; C495248:wnt8a protein, Xenopus; C008757:palmitoleic acid