Akkermans, Onno, Delloye-Bourgeois, Céline, Peregrina, Claudia et al. (21 more authors) (2022) GPC3-Unc5 receptor complex structure and role in cell migration. Cell. 3931-3949.e26. ISSN 1097-4172
Abstract
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.
Metadata
Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors | ||||
Keywords: | Animals, Cell Movement, Glypicans/chemistry, Humans, Mice, Mutant Proteins, Netrin Receptors/chemistry, Receptors, Cell Surface/metabolism, Single-Domain Antibodies, Thrombospondins | ||||
Dates: |
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Institution: | The University of York | ||||
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) | ||||
Funding Information: |
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Depositing User: | Pure (York) | ||||
Date Deposited: | 02 Nov 2022 16:50 | ||||
Last Modified: | 04 Feb 2024 01:20 | ||||
Published Version: | https://doi.org/10.1016/j.cell.2022.09.025 | ||||
Status: | Published | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1016/j.cell.2022.09.025 |
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Description: GPC3-Unc5 receptor complex structure and role in cell migration
Licence: CC-BY 2.5