Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly
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 o...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43148-8 |
| _version_ | 1797452102176342016 |
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| author | F. M. Houghton S. E. Adams A. S. Ríos L. Masino A. G. Purkiss D. C. Briggs F. Ledda N. Q. McDonald |
| author_facet | F. M. Houghton S. E. Adams A. S. Ríos L. Masino A. G. Purkiss D. C. Briggs F. Ledda N. Q. McDonald |
| author_sort | F. M. Houghton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:03:55Z |
| format | Article |
| id | doaj.art-62b3841fe5224ed7b815d95873e24a85 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T15:03:55Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-62b3841fe5224ed7b815d95873e24a852023-11-26T13:44:28ZengNature PortfolioNature Communications2041-17232023-11-0114111610.1038/s41467-023-43148-8Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assemblyF. M. Houghton0S. E. Adams1A. S. Ríos2L. Masino3A. G. Purkiss4D. C. Briggs5F. Ledda6N. Q. McDonald7Signalling and Structural Biology laboratory, The Francis Crick InstituteSignalling and Structural Biology laboratory, The Francis Crick InstituteFundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos AiresStructural Biology Science and Technology Platform, The Francis Crick InstituteStructural Biology Science and Technology Platform, The Francis Crick InstituteSignalling and Structural Biology laboratory, The Francis Crick InstituteFundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos AiresSignalling and Structural Biology laboratory, The Francis Crick InstituteAbstract 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.https://doi.org/10.1038/s41467-023-43148-8 |
| spellingShingle | F. M. Houghton S. E. Adams A. S. Ríos L. Masino A. G. Purkiss D. C. Briggs F. Ledda N. Q. McDonald Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly Nature Communications |
| title | Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly |
| title_full | Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly |
| title_fullStr | Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly |
| title_full_unstemmed | Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly |
| title_short | Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly |
| title_sort | architecture and regulation of a gdnf gfrα1 synaptic adhesion assembly |
| url | https://doi.org/10.1038/s41467-023-43148-8 |
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