ZFIN ID: ZDB-PUB-170214-292
RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association
Goodman, K.M., Kjær, S., Beuron, F., Knowles, P.P., Nawrotek, A., Burns, E.M., Purkiss, A.G., George, R., Santoro, M., Morris, E.P., McDonald, N.Q.
Date: 2014
Source: Cell Reports   8: 1894-904 (Journal)
Registered Authors: Santoro, Massimo
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Antibodies/immunology
  • Binding Sites
  • CHO Cells
  • Cell Membrane/metabolism*
  • Cricetinae
  • Cricetulus
  • Epitopes/immunology
  • Glial Cell Line-Derived Neurotrophic Factor/chemistry
  • Glial Cell Line-Derived Neurotrophic Factor/metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors/chemistry
  • Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics
  • Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism*
  • Humans
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-ret/chemistry
  • Proto-Oncogene Proteins c-ret/genetics
  • Proto-Oncogene Proteins c-ret/metabolism*
  • Rats
  • Recombinant Proteins/biosynthesis
  • Recombinant Proteins/chemistry
  • Recombinant Proteins/genetics
  • Sequence Alignment
  • Zebrafish
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 25242331 Full text @ Cell Rep.
ABSTRACT
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.
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