PUBLICATION
RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association
- Authors
- 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.
- ID
- ZDB-PUB-170214-292
- 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.
Citation
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. (2014) RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Cell Reports. 8:1894-904.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping