RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• Retinaldehyde-binding proteins (RTN4), also known as NoGo receptors, have poorly understood physiological roles and interactors.
• BAI adhesion G protein-coupled receptors (GPCRs) have diverse functions, but their ligands and specific roles remain unclear.

Purpose of the Study:

• To identify physiological interactors of RTN4 receptors.
• To elucidate the function of BAI adhesion GPCRs.
• To investigate the molecular basis of interactions between RTN4 receptors and BAI GPCRs.

Main Methods:

• Unbiased biochemical approaches to identify protein interactions.
• Structural analysis using X-ray crystallography (1.65 Å resolution).
• In vitro binding assays to determine affinity.
• Studies in human neurons to assess functional roles.

Main Results:

• RTN4 receptors were identified as high-affinity ligands for BAI adhesion GPCRs.
• A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all RTN4 receptor isoforms with nanomolar affinity.
• The crystal structure revealed that C-mannosylation and O-fucosylation of BAI TSR domains create a unique interface for high-affinity RTN4 receptor binding.
• In human neurons, RTN4 receptors differentially bind to glial versus neuronal BAIs to regulate dendritic arborization, axonal elongation, and synapse formation, thereby controlling neural network activity.

Conclusions:

• BAI binding to RTN4/NoGo receptors forms a critical receptor-ligand axis.
• Rare post-translational modifications (glycoconjugates) on BAI TSR domains are essential for high-affinity RTN4 receptor interactions.
• This axis plays a crucial role in controlling the development of synaptic circuits and neural network activity.