biostudies-literatureAkkermans OWellcome TrustEngineering and Physical Sciences Research Council3931-3949.e26https://www.ebi.ac.uk/biostudies/studies/S-EPMC9596381biostudies-literatureUnknown185(21)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, togetCellGPC3-Unc5 receptor complex structure and role in cell migration.PMC9596381EP/S025243/1EP/R029164/1202827/Z/16/ZChavent MZaballa SHuo JDel Toro DSeiradake EBen Amar DMcCubbin PTNOwens RJWhite ESDelloye-Bourgeois CPeregrina CRobinson CVBerbeira-Santana MComoletti DLowe EAkkermans OPakos IReynaud FAgirre JRaj RAksu MCarrasquero-Ordaz MKokolaki MCastellani VfalseGPC3-Unc5 receptor complex structure and role in cell migration.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, toget2022-01-01T00:00:00Z2022 Oct2026-05-03T10:34:16.076Z2024-10-14T23:04:53.917ZS-EPMC95963813624074010.1016/j.cell.2022.09.025