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TitleArchitecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 7551, Year 2023
Publish dateNov 20, 2023
AuthorsF M Houghton / S E Adams / A S Ríos / L Masino / A G Purkiss / D C Briggs / F Ledda / N Q McDonald /
PubMed AbstractGlial-cell line derived neurotrophic factor (GDNF) bound to its co-receptor GFRα1 stimulates the RET receptor tyrosine kinase, promoting neuronal survival and neuroprotection. The GDNF-GFRα1 ...Glial-cell line derived neurotrophic factor (GDNF) bound to its co-receptor GFRα1 stimulates the RET receptor tyrosine kinase, promoting neuronal survival and neuroprotection. The GDNF-GFRα1 complex also supports synaptic cell adhesion independently of RET. Here, we describe the structure of a decameric GDNF-GFRα1 assembly determined by crystallography and electron microscopy, revealing two GFRα1 pentamers bridged by five GDNF dimers. We reconsitituted the assembly between adhering liposomes and used cryo-electron tomography to visualize how the complex fulfils its membrane adhesion function. The GFRα1:GFRα1 pentameric interface was further validated both in vitro by native PAGE and in cellulo by cell-clustering and dendritic spine assays. Finally, we provide biochemical and cell-based evidence that RET and heparan sulfate cooperate to prevent assembly of the adhesion complex by competing for the adhesion interface. Our results provide a mechanistic framework to understand GDNF-driven cell adhesion, its relationship to trophic signalling, and the central role played by GFRα1.
External linksNat Commun / PubMed:37985758 / PubMed Central
MethodsEM (subtomogram averaging) / EM (tomography) / X-ray diffraction
Resolution2.66 - 21.7 Å
Structure data

EMDB-18400: GDNF/GFRa1 cell adhesion complex cryo-ET structure
Method: EM (subtomogram averaging) / Resolution: 21.7 Å

EMDB-18651: GDNF/GFRa1 cell adhesion complex bridging between adhering liposomes.
Method: EM (tomography)

PDB-8os6:
Structure of a GFRA1/GDNF LICAM complex
Method: X-RAY DIFFRACTION / Resolution: 2.66 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-HOH:
WATER / Water

Source
  • danio rerio (zebrafish)
KeywordsCELL ADHESION / Adhesion / Synapse / Complex / signalling

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