Academic Journal
Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity
| العنوان: | Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity |
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| المؤلفون: | Kumar, S., Zigman, M., Patel, T. R., Trageser, B., Gross, J. C., Rahm, K., Boutros, M., Gradl, D., Steinbeisser, H., Holstein, T., Stetefeld, J., Özbek, S. |
| المصدر: | BMC Biology, 12, 44 ; ISSN: 1741-7007 |
| بيانات النشر: | Springer Fachmedien Wiesbaden |
| سنة النشر: | 2015 |
| المجموعة: | KITopen (Karlsruhe Institute of Technologie) |
| مصطلحات موضوعية: | Wnt signaling, Wnt, Frizzled, Wnt3a mutation analysis, ddc:570, Life sciences, biology, info:eu-repo/classification/ddc/570 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/wos/000338467300003; info:eu-repo/semantics/altIdentifier/issn/1741-7007; https://publikationen.bibliothek.kit.edu/1000046386; https://publikationen.bibliothek.kit.edu/1000046386/3469956; https://doi.org/10.5445/IR/1000046386; http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:swb:90-463865 |
| DOI: | 10.5445/IR/1000046386 |
| الاتاحة: | https://publikationen.bibliothek.kit.edu/1000046386 https://publikationen.bibliothek.kit.edu/1000046386/3469956 https://doi.org/10.5445/IR/1000046386 http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:swb:90-463865 |
| Rights: | KITopen License, https://publikationen.bibliothek.kit.edu/kitopen-lizenz ; info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.75661059 |
| قاعدة البيانات: | BASE |
| DOI: | 10.5445/IR/1000046386 |
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