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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.

Original publication




Journal article



Publication Date





3931 - 3949.e26


GPC3, UNC5A, UNC5B, UNC5C, UNC5D, Unc5, cell guidance, cell migration, cortex development, crystallography, glypican-3, nanobodies, neuroblastoma, stripe assay, structural biology, surface plasmon resonance, uncoordinated-5, Animals, Carcinoma, Hepatocellular, Cell Movement, Glypicans, Humans, Liver Neoplasms, Mice, Mutant Proteins, Receptors, Cell Surface, Single-Domain Antibodies, Thrombospondins