RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association.
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The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RET(ECD)), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RET(ECD) envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET(ECD) cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation.
Version of record
Amino Acid Sequence
Protein Structure, Tertiary
Molecular Sequence Data
Proto-Oncogene Proteins c-ret
Glial Cell Line-Derived Neurotrophic Factor Receptors
Glial Cell Line-Derived Neurotrophic Factor
Structural Electron Microscopy
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Cell reports, 2014, 8 (6), pp. 1894 - 1904
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
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