Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly

DOI: 10.1038/s41467-023-43148-8

Authors: 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; Birkbeck, University of London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: November 2023
Diamond Proposal Number(s): 13775

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-drive

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 29/11/2023 13:32

Documents:
s41467-023-43148-8.pdf

Discipline Tags:

Health & Wellbeing Neurology Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)