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J. Biol. Chem., Vol. 283, Issue 24, 16641-16652, June 13, 2008

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Ganglioside Inhibition of Neurite Outgrowth Requires Nogo Receptor Function

IDENTIFICATION OF INTERACTION SITES AND DEVELOPMENT OF NOVEL ANTAGONISTS^*

Gareth Williams, Andrew Wood, Emma-Jane Williams, Ying Gao, Mary L. Mercado, Alan Katz, Diane Joseph-McCarthy, Brian Bates, Huai-Ping Ling, Ann Aulabaugh, Joe Zaccardi, Yuhong Xie, Menelas N. Pangalos, Frank S. Walsh, and Patrick Doherty¹

From the Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, United Kingdom and Neuroscience Discovery, Wyeth Research, Princeton, New Jersey 08543

Gangliosides are key players in neuronal inhibition, with antibody-mediated clustering of gangliosides blocking neurite outgrowth in cultures and axonal regeneration post injury. In this study we show that the ganglioside GT1b can form a complex with the Nogo-66 receptor NgR1. The interaction is shown by analytical ultracentrifugation sedimentation and is mediated by the sialic acid moiety on GT1b, with mutations in FRG motifs on NgR1 attenuating the interaction. One FRG motif was developed into a cyclic peptide (N-AcCLQKFRGSSC-NH₂) antagonist of GT1b, reversing the GT1b antibody inhibition of cerebellar granule cell neurite outgrowth. Interestingly, the peptide also antagonizes neurite outgrowth inhibition mediated by soluble forms of the myelin-associated glycoprotein (MAG). Structure function analysis of the peptide point to the conserved FRG triplet being the minimal functional motif, and mutations within this motif inhibit NgR1 binding to both GT1b and MAG. Finally, using gene ablation, we show that the cerebellar neuron response to GT1b antibodies and soluble MAG is indeed dependent on NgR1 function. The results suggest that gangliosides inhibit neurite outgrowth by interacting with FRG motifs in the NgR1 and that this interaction can also facilitate the binding of MAG to the NgR1. Furthermore, the results point to a rational strategy for developing novel ganglioside antagonists.

Received for publication, March 14, 2008

^* 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 Fig. 1.

¹ To whom correspondence should be addressed: The Wolfson Centre for Age-Related Diseases King's College London, Wolfson Wing Hodgkin Bldg., London SE1 1UL, UK. Tel.: 0207-848-6811; Fax: 0207-848-6816; E-mail: patrick.doherty{at}kcl.ac.uk.

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