Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins

The EMBO Journal, 2003 · DOI: · Published: May 13, 2003

Simple Explanation

The proteins Nogo, MAG, and OMgp inhibit axon regeneration after spinal cord and brain injuries by signaling through neuronal receptors containing a subunit called the Nogo-66 receptor (NgR). This study investigates how these proteins interact with NgR. The study found that the entire leucine-rich repeat (LRR) region of NgR is required for binding to soluble fragments of Nogo, MAG, and NgR. Two related proteins, NgR2 and NgR3, do not bind to these proteins despite sequence similarity. The crystal structure of NgR's ligand-binding ectodomain was determined, revealing a banana-shaped molecule with eight LRRs. Analysis of the structure and comparison with NgR2 and NgR3 identified potential protein interaction sites for functional signaling complex assembly.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Not specified

Key Findings

1
The entire LRR region of NgR is necessary for the binding of Nogo, MAG, and NgR itself to cell-surface NgR.
2
NgR2 and NgR3, despite sequence similarity to NgR, do not bind Nogo, MAG, or OMgp, suggesting functional divergence.
3
The crystal structure of NgR reveals a banana-shaped molecule with eight LRRs, an N-terminal cap, and a C-terminal subdomain, identifying potential protein interaction sites.

Research Summary

This study investigates the binding properties of the Nogo-66 receptor (NgR) and its related proteins, NgR2 and NgR3, to myelin-derived inhibitors of axon regeneration, Nogo, MAG, and OMgp. Deletion analysis reveals that the entire leucine-rich repeat (LRR) region of NgR is essential for binding to Nogo, MAG, and NgR. In contrast, NgR2 and NgR3 do not bind to these ligands, indicating distinct ligand-binding specificities despite sequence similarity. The crystal structure of the NgR ectodomain is determined, revealing a banana-shaped molecule with eight LRRs. This structure, along with comparisons to NgR2 and NgR3, identifies potential protein interaction sites important for assembling a functional signaling complex.

Practical Implications

Targeted Therapy Development

Understanding the specific interaction sites on NgR for its ligands can aid in developing targeted therapies to block inhibitory signaling and promote axon regeneration after CNS injury.

Selective Receptor Modulation

The differences in ligand binding between NgR and its related proteins, NgR2 and NgR3, suggest the possibility of developing selective modulators for each receptor to achieve specific therapeutic effects.

Co-receptor Interaction Insights

Identifying the protein interaction sites on NgR can help elucidate the mechanisms of co-receptor interactions, such as with p75NTR, and their roles in repulsive signaling.

Study Limitations

1
The study focuses on in vitro binding assays and structural analysis, lacking in vivo validation of the identified interaction sites.
2
The structure of NgR was determined at 3.2 AÊ resolution, which may limit the accuracy of detailed atomic interactions.
3
The study does not fully elucidate the specific mechanisms by which NgR2 and NgR3 exert their functions, as their ligands remain undetermined.

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