Distinct structural elements in GDNF mediate binding to GFRalpha 1 and activation of the GFRalpha 1-c-Ret receptor complex

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Abstract
Ligand‐induced receptor oligomerization is a widely accepted mechanism for activation of cell‐surface receptors. We investigated ligand–receptor interactions in the glial cell‐line derived neurotrophic factor (GDNF) receptor complex, formed by the c‐Ret receptor tyrosine kinase and the glycosylphosphatidylinositol (GPI)‐anchored subunit GDNF family receptor alpha‐1 (GFRα1). As only GFRα1 can bind GDNF directly, receptor complex formation is thought to be initiated by GDNF binding to this receptor. Here we identify an interface in GDNF formed by exposed acidic and hydrophobic residues that is critical for binding to GFRα1. Unexpectedly, several GDNF mutants deficient in GFRα1 binding retained the ability to bind and activate c‐Ret at normal levels. Although impaired in binding GFRα1 efficiently, these mutants still required GFRα1 for c‐Ret activation. These findings support a role for c‐Ret in ligand binding and indicate that GDNF does not initiate receptor complex formation, but rather interacts with a pre‐assembled GFRα1–c‐Ret complex.