1. GPC3-Unc5 receptor complex structure and role in cell migration.
- Author
-
Akkermans, Onno, Delloye-Bourgeois, Céline, Peregrina, Claudia, Carrasquero-Ordaz, Maria, Kokolaki, Maria, Berbeira-Santana, Miguel, Chavent, Matthieu, Reynaud, Florie, Raj, Ritu, Agirre, Jon, Aksu, Metin, White, Eleanor S., Lowe, Edward, Ben Amar, Dounia, Zaballa, Sofia, Huo, Jiandong, Pakos, Irene, McCubbin, Patrick T.N., Comoletti, Davide, and Owens, Raymond J.
- Subjects
- *
CELL anatomy , *CANCER cell migration , *CELL migration , *MUTANT proteins , *PYRAMIDAL neurons , *CANCER cells - 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. [Display omitted] • Uncoordinated-5 receptor D (Unc5D) and glypican-3 (GPC3) form an octameric complex • Anti-GPC3 nanobodies (Nanoglue, Nanobreak) enhance or weaken Unc5-GPC3 binding • Unc5/GPC3 signaling causes cell contact-repulsion in vitro • In vivo , Unc5/GPC3 modulate the migration of cortical neurons and neuroblastoma cells Detailed structural analysis and modulation of binding between uncoordinated-5 receptor D (Unc5D) and morphogen receptor glypican-3 (GPC3) reveal how finely balanced Unc5-GPC3 interactions regulate the migration of neuronal and cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF