ArticleScience advances2019
Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain.
Article in Science advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- RET receptor tyrosine kinase architecture, assemblies, and activation.Endocrine-related cancer · 2026Review
- Systematic structure-based analysis of RET variants in MEN2A and Hirschsprung's disease, and the paradoxical co-occurrence of both conditions.Disease models & mechanisms · 2026Article
- Design of Bicyclic Peptide Tandems Mimicking the Homodimeric GDF15 Protein to Inhibit GDF15-GFRaL-RET Complex Cell Signaling.Journal of medicinal chemistry · 2025Article
- BHLHE40 contributes to allergic asthma progression in mice through NRTN downregulation in macrophages.Communications biology · 2025Article
- Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly.Nature communications · 2023Article
- Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis.Cancer research · 2022Article
- Cryo-electron Microscopic Analysis of Single-Pass Transmembrane Receptors.Chemical reviews · 2022Review
- RET receptor signaling: Function in development, metabolic disease, and cancer.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2022Review
- Association between somatic RET mutations and clinical and genetic characteristics in patients with metastatic colorectal cancer.Cancer medicine · 2021Article
- A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing.Structure (London, England : 1993) · 2021Article
- Improving therapeutic potential of GDNF family ligands.Cell and tissue research · 2020Review
- Roles of theJMA journal · 2020Review
- Article
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Authors and funding
8 authors.
Funding
Abstract
Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRα2 and determined its structure at 5.7-Å resolution by cryo-EM. The proteins form an assembly through RET-GFRα2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFRα2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.
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