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

Kumar, Sumit ; Žigman, Mihaela ; Patel, Trushar R. ; Trageser, Benjamin ; Gross, Julia C. ; Rahm, Karolin ; Boutros, Michael ; Gradl, Dietmar ; Steinbeisser, Herbert ; Holstein, Thomas ; Stetefeld, Jörg ; Özbek, Suat

In: BMC biology, 12 (2014), Nr. 44. pp. 1-16. ISSN 1741-7007

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Download (1MB) | Lizenz: Creative Commons LizenzvertragMolecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity by Kumar, Sumit ; Žigman, Mihaela ; Patel, Trushar R. ; Trageser, Benjamin ; Gross, Julia C. ; Rahm, Karolin ; Boutros, Michael ; Gradl, Dietmar ; Steinbeisser, Herbert ; Holstein, Thomas ; Stetefeld, Jörg ; Özbek, Suat underlies the terms of Creative Commons Attribution 3.0 Germany

Official URL: http://dx.doi.org/10.1186/1741-7007-12-44
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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.

Item Type: Article
Journal or Publication Title: BMC biology
Volume: 12
Number: 44
Publisher: Springer
Place of Publication: Berlin ; Heidelberg
Date Deposited: 01 Dec 2015 13:48
Date: 2014
ISSN: 1741-7007
Page Range: pp. 1-16
Faculties / Institutes: Medizinische Fakultät Mannheim > Zentrum für Biomedizin und Medizintechnik (CBTM)
Service facilities > Centre for Organismal Studies Heidelberg (COS)
Medizinische Fakultät Heidelberg > Institut für Humangenetik
Subjects: 570 Life sciences
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