GPC3-Unc5 receptor complex structure and role in cell migration

Onno Akkermans, Céline Delloye-Bourgeois, Claudia Peregrina, Maria Carrasquero-Ordaz, Maria Kokolaki, Miguel Berbeira-Santana, Matthieu Chavent, Florie Reynaud, Ritu Raj, Jon Agirre, Metin Aksu, Eleanor S White, Edward Lowe, Dounia Ben Amar, Sofia Zaballa, Jiandong Huo, Irene Pakos, Patrick T N McCubbin, Davide Comoletti, Raymond J OwensCarol V Robinson, Valérie Castellani, Daniel Del Toro, Elena Seiradake

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3931-3949.e26
Number of pages46
Issue number21
Publication statusPublished - 13 Oct 2022

Bibliographical note

© 2022 The Authors


  • Animals
  • Cell Movement
  • Glypicans/chemistry
  • Humans
  • Mice
  • Mutant Proteins
  • Netrin Receptors/chemistry
  • Receptors, Cell Surface/metabolism
  • Single-Domain Antibodies
  • Thrombospondins

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