7ZA3

GPC3-Unc5D octamer structure and role in cell migration

Summary for 7ZA3

• Entry DOI: 10.2210/pdb7za3/pdb
• Descriptor: Glypican-3, Netrin receptor UNC5D, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: complex, cell migration, glycan-glycan interaction, signaling protein
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 8
• Total formula weight: 338388.11

Authors

Akkermans, O.,Delloye-Bourgeois, C.,Peregrina, C.,Carrasquero, M.,Kokolaki, M.,Berbeira-Santana, M.,Chavent, M.,Reynaud, F.,Ritu, R.,Agirre, J.,Aksu, M.,White, E.,Lowe, E.,Ben Amar, D.,Zaballa, S.,Huo, J.,Pakos, I.,McCubbin, P.,Comoletti, D.,Owens, R.,Robinson, C.,Castellani, V.,del Toro, D.,Seiradake, E. (deposition date: 2022-03-21, release date: 2022-11-02, Last modification date: 2024-10-23)

Primary citation

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, E.S.,Lowe, E.,Ben Amar, D.,Zaballa, S.,Huo, J.,Pakos, I.,McCubbin, P.T.N.,Comoletti, D.,Owens, R.J.,Robinson, C.V.,Castellani, V.,Del Toro, D.,Seiradake, E.
GPC3-Unc5 receptor complex structure and role in cell migration.
Cell, 185:3931-3949.e26, 2022

PubMed 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.

PubMed: 36240740
DOI: 10.1016/j.cell.2022.09.025

Experimental method

X-RAY DIFFRACTION (4 Å)