Nature Communications (Nov 2023)

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,
  • N. Q. McDonald

DOI
https://doi.org/10.1038/s41467-023-43148-8
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 16

Abstract

Read online

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.