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GPC3-Unc5D octamer structure and role in cell migrationGPC3-Unc5D octamer structure and role in cell migration
Structural highlights
FunctionUNC5D_RAT Receptor for the netrin NTN4 that promotes neuronal cell survival. Plays a role in cell-cell adhesion and cell guidance. Receptor for netrin involved in cell migration. Plays a role in axon guidance by mediating axon repulsion of neuronal growth cones in the developing nervous system upon ligand binding. May play a role in apoptosis in response to DNA damage. It also acts as a dependence receptor required for apoptosis induction when not associated with netrin ligand (By similarity). Mediates cell-cell adhesion via its interaction with FLRT3 on an adjacent cell (By similarity).[UniProtKB:Q6UXZ4][UniProtKB:Q8K1S2] Publication Abstract from PubMedNeural 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. GPC3-Unc5 receptor complex structure and role in cell migration.,Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E Cell. 2022 Oct 13;185(21):3931-3949.e26. doi: 10.1016/j.cell.2022.09.025. PMID:36240740[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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