Structural Basis of Wnt Recognition by Frizzled
- 6 July 2012
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 337 (6090), 59-64
- https://doi.org/10.1126/science.1222879
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.Keywords
This publication has 58 references indexed in Scilit:
- Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubilityProceedings of the National Academy of Sciences of the United States of America, 2011
- Structural and Functional Studies of LRP6 Ectodomain Reveal a Platform for Wnt SignalingDevelopmental Cell, 2011
- Structural Basis of Wnt Signaling Inhibition by Dickkopf Binding to LRP5/6Developmental Cell, 2011
- Crystal structures of the extracellular domain of LRP6 and its complex with DKK1Nature Structural & Molecular Biology, 2011
- Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1Nature Structural & Molecular Biology, 2011
- Reconstitution of a Frizzled8·Wnt3a·LRP6 Signaling Complex Reveals Multiple Wnt and Dkk1 Binding Sites on LRP6Published by Elsevier BV ,2010
- Wnt/β-Catenin Signaling: Components, Mechanisms, and DiseasesDevelopmental Cell, 2009
- A Wnt Survival Guide: From Flies to Human DiseaseJournal of Investigative Dermatology, 2009
- Inference of Macromolecular Assemblies from Crystalline StateJournal of Molecular Biology, 2007
- Function and biological roles of the Dickkopf family of Wnt modulatorsOncogene, 2006