Structural Basis of Wnt Recognition by Frizzled
SSRL Science
Summary - September 2012
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.1222879Related Links
Contacts
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.
