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

Kumar, S.; Zigman, M.; Patel, T. R.; Trageser, B.; Gross, J. C.; Rahm, K. 1; Boutros, M.; Gradl, D. 1; Steinbeisser, H.; Holstein, T.; Stetefeld, J.; Özbek, S.
1 Zoologisches Institut (ZOO), Karlsruher Institut für Technologie (KIT)

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.

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Volltext §
DOI: 10.5445/IR/1000046386
Originalveröffentlichung
DOI: 10.1186/1741-7007-12-44
Scopus
Zitationen: 21
Web of Science
Zitationen: 21
Dimensions
Zitationen: 26
Cover der Publikation
Zugehörige Institution(en) am KIT Zoologisches Institut (ZOO)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2014
Sprache Englisch
Identifikator ISSN: 1741-7007
urn:nbn:de:swb:90-463865
KITopen-ID: 1000046386
Erschienen in BMC Biology
Verlag Springer Fachmedien Wiesbaden
Band 12
Seiten 44
Schlagwörter Wnt signaling; Wnt; Frizzled; Wnt3a mutation analysis
Nachgewiesen in Dimensions
Scopus
Web of Science
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