Architecture and regulation of a GDNF-GFRa1 synaptic adhesion assembly

Houghton, F.M. and Adams, S.E. and Rios, A.S. and Masino, L. and Purkiss, A.G. and Briggs, D.C. and Ledda, F. and McDonald, Neil Q. (2023) Architecture and regulation of a GDNF-GFRa1 synaptic adhesion assembly. Nature Communications , ISSN 2041-1723. (Submitted)

Abstract

Glial-cell line derived neurotrophic factor (GDNF) bound to its co-receptor GFRa1 stimulates the RET receptor tyrosine kinase, promoting neuronal survival and neuroprotection. The GDNF-GFRa1 complex also acts as a synaptic cell adhesion independently of RET. Here, we describe the structure of a decameric GDNF-GFRa1 assembly determined by crystallography and electron microscopy, revealing two GFRa1 pentamers bridged by five GDNF dimers. We reconsitituted the assembly in vitro between pairs of adhering liposomes and used cryo-electron tomography to visualize how the complex fulfils its membrane adhesion function. The GFRa1:GFRa1 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 of GFRa1. Houghton, FM1, Adams SE^1, Ríos AS2, Masino, L3, Purkiss AG3, Briggs DC1, Ledda, F2, & McDonald N.Q.1,4,

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