GPC3-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 glypi...
| Prif Awduron: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Fformat: | Journal article |
| Iaith: | English |
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Cell Press
2022
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| _version_ | 1826308586564747264 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Akkermans, O |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:21:35Z |
| format | Journal article |
| id | oxford-uuid:a0fca914-957b-46a2-b7e0-6be9aa826108 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:21:35Z |
| publishDate | 2022 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:a0fca914-957b-46a2-b7e0-6be9aa8261082022-10-18T10:52:11ZGPC3-Unc5 receptor complex structure and role in cell migrationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a0fca914-957b-46a2-b7e0-6be9aa826108EnglishSymplectic ElementsCell Press2022Akkermans, ODelloye-Bourgeois, CPeregrina, CCarrasquero-Ordaz, MKokolaki, MBerbeira-Santana, MChavent, MReynaud, FRaj, RAgirre, JAksu, MWhite, ESLowe, EBen Amar, DZaballa, SHuo, JPakos, IMcCubbin, PTNComoletti, DOwens, RJRobinson, CVCastellani, Vdel Toro, DSeiradake, ENeural 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. |
| spellingShingle | 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 GPC3-Unc5 receptor complex structure and role in cell migration |
| title | GPC3-Unc5 receptor complex structure and role in cell migration |
| title_full | GPC3-Unc5 receptor complex structure and role in cell migration |
| title_fullStr | GPC3-Unc5 receptor complex structure and role in cell migration |
| title_full_unstemmed | GPC3-Unc5 receptor complex structure and role in cell migration |
| title_short | GPC3-Unc5 receptor complex structure and role in cell migration |
| title_sort | gpc3 unc5 receptor complex structure and role in cell migration |
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