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J. Biol. Chem., Vol. 282, Issue 8, 5715-5725, February 23, 2007

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Characterization of Myelin Ligand Complexes with Neuronal Nogo-66 Receptor Family Members^*

Juha Laurén, Fenghua Hu, Joanna Chin, Ji Liao, Matti S. Airaksinen, and Stephen M. Strittmatter¹

From the Departments of Neurology and Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520 and the Neuroscience Center, University of Helsinki, FIN-00014 Helsinki, Finland

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 injury. Within Nogo-A, two separate domains are known interact with NgR1. NgR1 is the founding member of the three-member NgR family, whereas Nogo-A (RTN4A) belongs to a four-member reticulon family. Here, we systematically mapped the interactions between these superfamilies, demonstrating novel nanomolar interactions of RTN2 and RTN3 with NgR1. Because RTN3 is expressed in 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 confirmed here that MAG binds to NgR2, but not to NgR3. Unexpectedly, we found that OMgp interacts with MAG with a higher affinity compared with 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 the NgR1 leucine-rich repeat domain and surrounded by differentially utilized residues. This detailed knowledge of the molecular interactions between NgR1 and its ligands is imperative when assessing options for development of NgR1-based therapeutics for central nervous system injuries.

Received for publication, October 17, 2006

^* This work was supported by National Institutes of Health Grants NS42304 and NS39962 and Biogen Idec (to S. M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 and Ref. 1.

¹ To whom correspondence should be addressed: Dept. of Neurology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Tel.: 203-785-4878; Fax: 203-785-5098; E-mail: stephen.strittmatter{at}yale.edu.

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