CHARACTERIZATION OF MYELIN LIGAND COMPLEXES WITH THE NEURONAL NOGO-66 RECEPTOR FAMILY

J Biol Chem, 2007 · DOI: 10.1074/jbc.M609797200 · Published: February 23, 2007

Simple Explanation

When nerve fibers of the brain and spinal cord in adult mammals are severed, little to no regrowth occurs. Astroglial scar and CNS myelin pose extrinsic barriers to regeneration. From CNS myelin, at least three proteins capable of inhibiting axonal growth in vitro are recognized: Nogo-A, MAG and OMgp Nogo-66 binding provided the basis for the identification of a receptor for Nogo-A, termed NgR or NgR1. Remarkably, MAG and OMgp also bind to NgR1 to inhibit axonal growth in vitro The molecular basis for NgR1 interaction with multiple ligands has not been defined. LRR domains are commonly involved in protein-protein interactions, presumably because the non- globular extended surface of LRR domain provides ample opportunities for high affinity interactions.

Study Duration

Not specified

Participants

COS-7 cells, HEK293T cells, adult mice

Evidence Level

Not specified

Key Findings

1
RTN2 and RTN3 interact with NgR1 with nanomolar affinity, suggesting a role in myelin inhibition of axonal growth.
2
Nogo-A interacts with NgR1 at three separate sites, suggesting a trivalent interaction.
3
OMgp interacts with MAG with a higher affinity than its affinity to NgR1.

Research Summary

The current study extends our understanding of how myelin inhibitors interact with the NgR family: NgR1 binds three linear segments of Nogo-A as well as MAG and OMgp; mutagenesis defined overlapping NgR1 binding sites for different ligands; RTN2 and RTN3 also bind NgR1 with high affinity; NgR2 binds MAG but not RTNs; and finally, NgR3 binds none of the known NgR family ligands Novel ligand-receptor interactions were elucidated so that future studies can characterize them in greater functional detail. The identification of a central ligand binding domain holds the promise that general NgR1 antagonists regeneration after CNS injury.

Practical Implications

Therapeutic Development

The identification of a central binding domain shared by multiple ligands may facilitate the design and development of small molecule therapeutics blocking all NgR1 ligands, potentially promoting axonal regeneration after CNS injury.

Understanding Redundancy

Mapping interactions between myelin inhibitory ligands and related molecules and NgR family members gives us better insight on the possible redundancy in signaling pathways.

Targeted Therapies

Detailed knowledge of the molecular interactions between NgR1 and its ligands is imperative when assessing the options to develop NgR1-based therapeutics for CNS injuries.

Study Limitations

1
Adaptive compensation for chronic genetic loss of NgR1 or Nogo-A may explain unclear genetic evidence.
2
Redundancy amongst the myelin inhibitory proteins and their signaling pathways.
3
Higher-resolution mapping of NgR1 residues involved in ligand-binding could reveal differences in their binding sizes.

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