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Science 337 (6090): 59-64

Copyright © 2012 by the American Association for the Advancement of Science

Structural Basis of Wnt Recognition by Frizzled

Claudia Y. Janda,1,2 Deepa Waghray,1,2 Aron M. Levin,1,2 Christoph Thomas,1,2 K. Christopher Garcia1,2,*

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.

1 Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
2 Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

* To whom correspondence should be addressed. E-mail: kcgarcia{at}stanford.edu


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