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Distinct structural elements in GDNF mediate binding to GFRα1 and activation of the GFRα1–c‐Ret receptor complex
Author(s) -
Eketjäll Susanna,
Fainzilber Michael,
MurrayRust Judith,
Ibáñez Carlos F.
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.21.5901
Subject(s) - glial cell line derived neurotrophic factor , gdnf family of ligands , biology , proto oncogene proteins c ret , microbiology and biotechnology , receptor , receptor tyrosine kinase , neurotrophic factors , signal transduction , biochemistry
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.