Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly

F. M. Houghton, S. E. Adams, A. S. Ríos, L. Masino, A. G. Purkiss, D. C. Briggs, F. Ledda and N. Q. McDonald ()
Additional contact information
F. M. Houghton: The Francis Crick Institute
S. E. Adams: The Francis Crick Institute
A. S. Ríos: Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires
L. Masino: The Francis Crick Institute
A. G. Purkiss: The Francis Crick Institute
D. C. Briggs: The Francis Crick Institute
F. Ledda: Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires
N. Q. McDonald: The Francis Crick Institute

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43148-8

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