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Structural Basis of Wnt Recognition by Frizzled
SSRL Science Summary - September 2012

Figure 1.
XWnt8 has an unusual two-domain structure.

Wnts are a family of signaling proteins that regulate the development and growth of an organism, as well as tissue regeneration and wound healing. Misregulated Wnt signaling is associated with the development of many types of cancers, including colon cancer, breast cancer and melanoma, and degenerative diseases like multiple sclerosis, Alzheimer's and Type 2 diabetes. Understanding of how Wnt proteins bind and activate Frizzled receptors is important for the development of effective anti-Wnt and anti-Frizzled drugs for the treatment of Wnt-related disease.

To understand how Wnts function, a team of researchers from Stanford University led by Prof. Christopher Garcia set out to determine the first 3D image of an isolated Wnt-Frizzled complex using macromolecular crystallography. However, Wnt proteins present a number of challenges due to lipid modifications and very poor expression. The biochemical studies showed that the cysteine-rich domain (CRD) of Frizzled, the primary Wnt binding domain, is able to solubilize Wnts in aqueous solution. They were able to grow crystals of Xenopus Wnt8 (XWnt8) bound to Frizzled 8-CRD and to determine the 3D structure of this complex using SSRL's Beam Line 11-1.

The structure of XWnt8 resembles a fist with extended index finger and thumb, which pinch the globular Fz8-CRD on opposite sites. The tip of the thumb is extended by the attached lipid, which binds in a deep and long groove in the CRD, shielding the lipid from the aqueous environment. The tip of the index finger binds to a wide and shallow groove in the opposite side on the CRD, mediating Wnt/Frizzled-specific interactions, and thus is primarily responsible for Wnt- Frizzled discrimination. This work will facilitate future biochemical and structural effort to elucidate the mechanism of Wnt signaling, and the development of therapeutics to target Wnt signaling.


Primary Citation

Structural Basis of Wnt Recognition by Frizzled. Claudia Y. Janda, Deepa Waghray, Aron M. Levin, Christoph Thomas, and K. Christopher Garcia. Science. 337, 59-64, 2012. doi: 10.1126/science.1222879

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Claudia Y. Janda and K. Christopher Garcia
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

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