Author:
Akkermans O,Delloye-Bourgeois C,Peregrina C,Carrasquero-Ordaz M,Kokolaki M,Berbeira-Santana M,Chavent M,Reynaud F,Raj Ritu,Agirre J,Aksu M,White E,Lowe E,Ben Amar D,Zaballa S,Huo J,McCubbin P.T.N.,Comoletti D,Owens R,Robinson C.V.,Castellani V,del Toro D,Seiradake E
Abstract
SummaryNeural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass-spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding. Using these tools in vivo, we show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell-guidance, with the potential for wide- ranging biomedical implications in development and cancer biology.
Publisher
Cold Spring Harbor Laboratory