Science, published online 31 May 2012, doi:10.1126/science.1222879

Credit: CHRIS GARCIA

Wnts are secreted glycoproteins that mediate growth and development via multiple signaling pathways, most of which rely on interaction with a Frizzled (Fz) receptor. There are numerous Wnts and Fz receptors, so the potential for complexity in this pathway is high. There is a dearth of understanding of the specificity of Wnt-Fz interactions because little structural information is available. Janda et al. report a Wnt–Fz crystal structure, providing the first structure of any Wnt and the first ligand-bound structure of Fz. To generate sufficient amounts of the complex, the authors expressed Xenopus Wnt8 (XWnt8) together with an Fc-Fz8 cysteine-rich domain. The resulting crystals contained glycosylated Wnt and yielded X-ray data resolved to 3.25 Å. XWnt8 formed a unique fold, consisting of two domains, an N-terminal α-helical domain and a C-terminal cysteine-rich region, which interact independently with Fz8; a lipid modification on Wnt largely determined the site 1 interaction with Fz. On the basis of the structure of XWnt8, the authors engineered mini-Wnt, a water-soluble subdomain from the C terminus, and demonstrated that this domain, which forms site 2, is largely responsible for discriminating among Fz receptors. Using surface plasmon resonance, the authors also demonstrated that mini-Wnt bound distinct Fz receptors with moderate but disparate affinities. Taken together, these data provide evidence for the polyspecificity of the Wnt-Fz interaction based on amino acids located at the site 1 and 2 interfaces.