dc.contributor.author	Kumar, Sumit
dc.contributor.author	Žigman, Mihaela
dc.contributor.author	Patel, Trushar R
dc.contributor.author	Trageser, Benjamin
dc.contributor.author	Gross, Julia C
dc.contributor.author	Rahm, Karolin
dc.contributor.author	Boutros, Michael
dc.contributor.author	Gradl, Dietmar
dc.contributor.author	Steinbeisser, Herbert
dc.contributor.author	Holstein, Thomas
dc.contributor.author	Stetefeld, Jörg
dc.contributor.author	Özbek, Suat
dc.date.accessioned	2014-06-24T15:19:15Z
dc.date.available	2014-06-24T15:19:15Z
dc.date.issued	2014-05-30
dc.date.updated	2014-06-24T15:19:16Z
dc.description.abstract	Abstract Background Wnt proteins are a family of secreted signaling molecules that regulate key developmental processes in metazoans. The molecular basis of Wnt binding to Frizzled and LRP5/6 co-receptors has long been unknown due to the lack of structural data on Wnt ligands. Only recently, the crystal structure of the Wnt8-Frizzled8-cysteine-rich-domain (CRD) complex was solved, but the significance of interaction sites that influence Wnt signaling has not been assessed. Results Here, we present an extensive structure-function analysis of mouse Wnt3a in vitro and in vivo. We provide evidence for the essential role of serine 209, glycine 210 (site 1) and tryptophan 333 (site 2) in Fz binding. Importantly, we discovered that valine 337 in the site 2 binding loop is critical for signaling without contributing to binding. Mutations in the presumptive second CRD binding site (site 3) partly abolished Wnt binding. Intriguingly, most site 3 mutations increased Wnt signaling, probably by inhibiting Wnt-CRD oligomerization. In accordance, increasing amounts of soluble Frizzled8-CRD protein modulated Wnt3a signaling in a biphasic manner. Conclusions We propose a concentration-dependent switch in Wnt-CRD complex formation from an inactive aggregation state to an activated high mobility state as a possible modulatory mechanism in Wnt signaling gradients.
dc.description.version	Peer Reviewed
dc.identifier.citation	BMC Biology. 2014 May 30;12(1):44
dc.identifier.doi	http://dx.doi.org/10.1186/1741-7007-12-44
dc.identifier.uri	http://hdl.handle.net/1993/23644
dc.language.rfc3066	en
dc.rights	open access	en_US
dc.rights.holder	Sumit Kumar et al.; licensee BioMed Central Ltd.
dc.title	Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity
dc.type	Journal Article

Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity

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