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Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly

Author

Listed:
  • F. M. Houghton

    (The Francis Crick Institute)

  • S. E. Adams

    (The Francis Crick Institute
    Vertex Pharmaceuticals)

  • 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 College)

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.

Suggested Citation

  • F. M. Houghton & S. E. Adams & A. S. Ríos & L. Masino & A. G. Purkiss & D. C. Briggs & F. Ledda & N. Q. McDonald, 2023. "Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43148-8
    DOI: 10.1038/s41467-023-43148-8
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    References listed on IDEAS

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    1. Charlotte H. Coles & Nikolaos Mitakidis & Peng Zhang & Jonathan Elegheert & Weixian Lu & Andrew W. Stoker & Terunaga Nakagawa & Ann Marie Craig & E. Yvonne Jones & A. Radu Aricescu, 2014. "Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    2. Jer-Yuan Hsu & Suzanne Crawley & Michael Chen & Dina A. Ayupova & Darrin A. Lindhout & Jared Higbee & Alan Kutach & William Joo & Zhengyu Gao & Diana Fu & Carmen To & Kalyani Mondal & Betty Li & Avant, 2017. "Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15," Nature, Nature, vol. 550(7675), pages 255-259, October.
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