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GPC3-Unc5 receptor complex structure and role in cell migration

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journal contribution
posted on 2023-03-19, 22:52 authored by O Akkermans, C Delloye-Bourgeois, C Peregrina, M Carrasquero-Ordaz, M Kokolaki, M Berbeira-Santana, M Chavent, F Reynaud, R Raj, J Agirre, M Aksu, ES White, E Lowe, D Ben Amar, S Zaballa, J Huo, I Pakos, PTN McCubbin, Davide ComolettiDavide Comoletti, RJ Owens, CV Robinson, V Castellani, D del Toro, E Seiradake
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.

Funding

Collaborative Research: Structure and Function of Reelin in Brain Development | Funder: RUTGERS UNIVERSITY | Grant ID: 1755189

History

Preferred 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.,... Seiradake, E. (2022). GPC3-Unc5 receptor complex structure and role in cell migration. Cell, 185(21), 3931-3949.e26. https://doi.org/10.1016/j.cell.2022.09.025

Journal title

Cell

Volume

185

Issue

21

Publication date

2022-10-13

Pagination

3931-3949.e26

Publisher

Elsevier BV

Publication status

Published

ISSN

0092-8674

eISSN

1097-4172

Language

en