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GPC3-Unc5 receptor complex structure and role in cell migration

Onno Akkermans1, Céline Delloye-Bourgeois2, Claudia Peregrina3

  • 1Department of Biochemistry, University of Oxford, Oxford, UK.

Cell
|October 14, 2022
PubMed

Insights

This study reveals the structure of Uncoordinated-5 receptor D (Unc5D) bound to glypican-3 (GPC3), uncovering how their interactions guide neural cell migration and cancer cell dissemination.

Area of Science:

  • Neuroscience
  • Structural Biology
  • Cancer Biology

Background:

  • Neural migration is crucial for brain development, involving cell-surface guidance receptors.
  • Cancer cells exploit these developmental mechanisms for metastasis.

Purpose of the Study:

  • To elucidate the structural basis of Uncoordinated-5 receptor D (Unc5D) and glypican-3 (GPC3) interactions.
  • To understand the role of Unc5D-GPC3 complexes in cell guidance during development and cancer.

Main Methods:

  • X-ray crystallography to determine the octameric complex structure.
  • Molecular dynamics simulations and mass spectrometry for validation.
  • Structure-based mutagenesis and nanobody assays in mouse and xenograft models.

Main Results:

  • Crystal structures revealed an octameric Unc5D-GPC3 complex with central glycan-glycan interactions.
  • N-linked glycans from GPC3 and C-mannosylated tryptophans of Unc5D mediate binding.
  • Unc5D-GPC3 interactions were shown to guide pyramidal neuron migration and neuroblastoma cell dissemination.

Conclusions:

  • A conserved structural mechanism for cell guidance mediated by Unc5D-GPC3 interactions was demonstrated.
  • Finely balanced Unc5D-GPC3 binding is critical for regulating cell migration in both development and disease.
Keywords:
GPC3UNC5AUNC5BUNC5CUNC5DUnc5cell guidancecell migrationcortex developmentcrystallographyglypican-3nanobodiesneuroblastomastripe assaystructural biologysurface plasmon resonanceuncoordinated-5

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