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A molecular mechanism for Wnt ligand-specific signaling

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Eubelen, Marie Bostaille, Naguissa Cabochette, Pauline Gauquier, Anne Tebabi, Patricia Dumitru, Andra-Cristina [UCL] Köhler, Melanie [UCL] Alsteens, David [UCL] Vanhollebeke, Benoit

Wnt signaling is key to many developmental, physiological and disease processes, in which cells seem able to discriminate between multiple Wnt ligands. This selective Wnt recognition or “decoding” capacity has remained enigmatic as Wnt/Frizzled interactions are largely incompatible with mono-specific recognition. Gpr124 and Reck enable brain endothelial cells to selectively respond to Wnt7. We show that Reck binds with low micromolar affinity to the intrinsically disordered linker region of Wnt7. Availability of Reck-bound Wnt7 for Frizzled signaling relies on the interaction between Gpr124 and Dishevelled. By polymerization, Dishevelled recruits Gpr124 and the associated Reck-bound Wnt7 into dynamic Wnt/Frizzled/Lrp5/6 signalosomes, resulting in increased local concentrations of Wnt7 available for Frizzled signaling. This work provides mechanistic insights into the Wnt decoding capacities of vertebrate cells and unravels structural determinants of the functional diversification of Wnt family members.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2018
Language Anglais
Journal information "Science" - Vol. 361, no.6403, p. eaat1178 (2018)
Peer reviewed yes
Publisher American Association for the Advancement of Science (AAAS)
issn 0036-8075
e-issn 1095-9203
Publication status Publié
Affiliation UCL - SST/LIBST - Louvain Institute of Biomolecular Science and Technology
Keywords Multidisciplinary
Links
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Bibliographic reference Eubelen, Marie ; Bostaille, Naguissa ; Cabochette, Pauline ; Gauquier, Anne ; Tebabi, Patricia ; et. al. A molecular mechanism for Wnt ligand-specific signaling. In: Science, Vol. 361, no.6403, p. eaat1178 (2018)
Permanent URL http://hdl.handle.net/2078.1/208813