RETStruc

Structure of the GRFa-1GNDF System

 

GDNF (glial cell line-derived neurotrophic factor) and related molecules (GDNF family ligands: GFLs) are critical in the control of neuronal survival and differentiation, kidney morphogenesis and spermatogenesis{Formatting Citation}. This occurs through the RET tyrosine kinase receptor. An intact GDNF-GFRα1-RET signaling system is essential for maintenance of substantia nigra dopaminergic neurons, the neurons affected in Parkinson’s disease in humans; and GDNF has been shown to be neuroprotective both in animal models and in phase I clinical trials. Gain-of-function mutations in RET cause carcinomas and neoplasias, while loss of function leads to Hirschsprung’s disease (lack of inervation of the colon).

In the classical GFL signaling pathway, GFLs activate RET via a specific GPI-anchored GFL coreceptor α (GFRα); four different GFLs act through four specific co-receptors: GDNF via GFRα1, neurturin via GFRα2, artemin via GFRα3, and persephin via GFRα4. However, crosstalk between them is observed. In general, homodimeric GFL binds its cognate GFRα and dimerises it. This heterotetrameric structure recruits two molecules of RET to form the RET2GFR2GDNF2 complex. Dimerization of the extracellular domains (ECD) of RET orients the intracellular domains (ICD), which have tyrosine kinase activity. Reciprocal phosphorylation on several tyrosine residues activates downstream pathways, including RAS/ERK, PI3K/AKT, cascades that control proliferation, differentiation and survival{Formatting Citation}.

We have recently solved multiple structures of the GFRα1-GDNF heterodimeric complex. GFRα1 clearly dimerises only through GDNF; the GFRα1 monomers do not interact (1,2). Unlike the artemin-GFRα3 structure (3), the GDNF-GFRα1 structure is bent, with the two GFRα1s pointing towards each other. This difference may be important for signalling (2). Our work shows that the heparin- and RET-binding regions on GFRα1 overlap. This may be how GDNF-induced hippocampal neuron adhesion and presynaptic differentiation occurs (2), and it may also explain how exogenous heparin can inhibit RET phosphorylation.

1. Parkash, V. & Goldman, A. (2009) Acta Crystallogr F 65, 551-58.
2. Parkash, V., Leppänen, V.-M. et al. (2008) J Biol Chem 283, 35164-72.
3. Wang, X., Baloh, R. H. et al. (2006) Structure 14, 1083-92