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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
Summary
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.
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