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Papers In Press, published online ahead of print December 21, 2006
Neurology, Yale Univ. School of Medicicne, New Haven, CT 06520
Corresponding Author: stephen.strittmatter{at}yale.edu
Nogo, MAG, and OMgp are myelin-associated proteins that bind to a neuronal Nogo-66 receptor (NgR/NgR1) to limit axonal regeneration after central nervous system (CNS) injury. Within Nogo-A two separate domains are known interact with NgR1. NgR1 is the founding member of three-member NgR family, whereas Nogo-A (RTN4-A) belongs to a four-member reticulon family. Here, we systematically map the interactions between these superfamilies, demonstrating novel nanomolar interactions of RTN2 and RTN3 with NgR1. Since RTN3 is expressed in the spinal cord white matter it may have a role in myelin inhibition of axonal growth. Further analysis of the Nogo-A and NgR1 interactions revealed a novel third interaction site between the proteins suggesting a trivalent Nogo-A interaction with NgR1. We also confirm here that MAG binds to NgR2, but not to NgR3. Unexpectedly, we found that OMgp interacts with MAG with a higher affinity than its affinity to NgR1. To better define how these multiple structurally distinct ligands bind to NgR1, we examined a series of Ala-substituted NgR1 mutants for ligand binding activity. We found that the core of the binding domain is centered in the middle of the concave surface of NgR1 leucine-rich repeat (LRR) domain and surrounded by differentially utilized residues. This 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.
J. Biol. Chem, 10.1074/jbc.M609797200
Submitted on October 17, 2006
Accepted on December 21, 2006
Characterization of myelin ligand complexes with the neuronal NOGO-66 receptor family
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