Abstract
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 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference89 articles.
1. Südhof, T. C. The cell biology of synapse formation. J. Cell Biol. 220, e202103052 (2021).
2. Washbourne, P. et al. Cell adhesion molecules in synapse formation. J. Neurosci. 24, 9244–9249 (2004).
3. Dalva, M. B., McClelland, A. C. & Kayser, M. S. Cell adhesion molecules: signalling functions at the synapse. Nat. Rev. Neurosci. 8, 206–220 (2007).
4. Ledda, F., Paratcha, G., Sandoval-Guzmán, T. & Ibá̃ez, C. F. GDNF and GFRα1 promote formation of neuronal synapses by ligand-induced cell adhesion. Nature Neuroscience 2007 10:3 10, 293–300 (2007).
5. Ledda, F. Ligand-induced cell adhesion as a new mechanism to promote synapse formation. Cell Adh. Migr. 1, 137–139 (2007).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献