GPC3-Unc5 receptor complex structure and role in cell migration

Journal article

Neural 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 and, together with mutant proteins, 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, where finely balanced Unc5-GPC3 interactions regulate cell migration.

Authors: Akkermans, O; Delloye-Bourgeois, C; Peregrina, C; Carrasquero-Ordaz, M; Kokolaki, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cell
• Volume: 185
• Issue: 21
• Pages: 3931-3949.e26
• Publication date: 2022-10-13
• Acceptance date: 2022-09-15
• DOI: 10.1016/j.cell.2022.09.025
• EISSN: 1097-4172
• ISSN: 0092-8674
• Language: English
• Keywords: FFR