RET receptor tyrosine kinase architecture, assemblies, and activation

Area of Science:

• Molecular Biology
• Cell Signaling
• Structural Biology

Background:

• The RET receptor tyrosine kinase is unique among 58 human RTKs for its extracellular cadherin-like domains.
• These domains form a binding site for glial-cell line derived neurotrophic factor (GDNF) family ligands (GFLs) complexed with GFR⍺ (GDNF family receptor alpha) co-receptors.

Purpose of the Study:

• To explore how the structure and architecture of the RET receptor facilitate flexible GFL-GFR⍺ binding.
• To summarize recent advancements in understanding RET structure.
• To discuss how distinct GFL-GFR⍺-RET complexes activate RET tyrosine kinase signaling.

Main Methods:

• Structural analysis of the RET receptor and its ligand-binding module.
• Review of recent literature on RET structure and function.
• Analysis of GFL-GFR⍺-RET complex assembly and activation mechanisms.

Main Results:

• The RET extracellular module exhibits a flexible binding site architecture for GFL-GFR⍺ ligands.
• Recent structural studies provide insights into RET's conformation and ligand interactions.
• Distinct complex formations dictate the activation of RET's intrinsic tyrosine kinase activity.

Conclusions:

• The structural flexibility of RET is key to its function.
• Understanding RET complex assembly is crucial for elucidating intracellular signal relay.
• This review highlights the interplay between RET structure, ligand binding, and kinase activation.