PUBLICATION
A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing
- Authors
- Adams, S.E., Purkiss, A.G., Knowles, P.P., Nans, A., Briggs, D.C., Borg, A., Earl, C.P., Goodman, K.M., Nawrotek, A., Borg, A.J., McIntosh, P.B., Houghton, F.M., Kjær, S., McDonald, N.Q.
- ID
- ZDB-PUB-210124-6
- Date
- 2021
- Source
- Structure (London, England : 1993) 29(7): 694-708.e7 (Journal)
- Registered Authors
- Keywords
- GDNF family ligands, RET, X-ray crystallography, co-receptor, cryo-EM, cystine knot, glycosylation, ligand recognition, receptor tyrosine kinase
- MeSH Terms
-
- Animals
- Cadherins/metabolism
- Cryoelectron Microscopy
- Crystallography, X-Ray
- Glial Cell Line-Derived Neurotrophic Factor/metabolism*
- Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism*
- Models, Molecular
- Multiprotein Complexes/chemistry
- Protein Binding
- Protein Conformation
- Protein Domains
- Proto-Oncogene Proteins c-ret/chemistry
- Proto-Oncogene Proteins c-ret/metabolism*
- Zebrafish/metabolism*
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/metabolism*
- PubMed
- 33484636 Full text @ Structure
Citation
Adams, S.E., Purkiss, A.G., Knowles, P.P., Nans, A., Briggs, D.C., Borg, A., Earl, C.P., Goodman, K.M., Nawrotek, A., Borg, A.J., McIntosh, P.B., Houghton, F.M., Kjær, S., McDonald, N.Q. (2021) A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing. Structure (London, England : 1993). 29(7):694-708.e7.
Abstract
RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2 and CLD3. Comparison with a cryo-electron microscopy structure of a ligand-engaged zebrafish RETECD-GDNF-GFRα1a complex indicates conformational changes within a clade-specific CLD3 loop adjacent to the co-receptor. Our observations indicate that RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFRα co-receptors, while its rigid arm recognizes a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualize linear arrays of RETECD-GDNF-GFRα1a suggesting that a conserved contact stabilizes higher-order species. Our study reveals that ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping