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Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides

Nature Biotechnology volume 17, pages 1000–1005 (1999)Cite this article

An Erratum to this article was published on 01 May 2000

Abstract

The neural cell adhesion molecule (NCAM) plays a key role in neural development, regeneration, and learning. In this study, we identified a synthetic peptide-ligand of the NCAM Ig1 module by combinatorial chemistry and showed it could modulate NCAM-mediated cell adhesion and signal transduction with high potency. In cultures of dissociated neurons, this peptide, termed C3, stimulated neurite outgrowth by activating a signaling pathway identical to that activated by homophilic NCAM binding. A similar effect was shown for the NCAM Ig2 module, the endogenous ligand of NCAM Ig1. By nuclear magnetic resonance spectroscopy, the C3 binding site in the NCAM Ig1 module was mapped and shown to be different from the binding site of the NCAM Ig2 module. The C3 peptide may prove useful as a lead in development of therapies for neurodegenerative disorders, and the C3 binding site of NCAM Ig1 may represent a target for discovery of nonpeptide drugs.

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Figure 1: Effect of NCAM Ig1 binding peptides on cell adhesion.
Figure 2: Effect of C3d on neurite outgrowth.
Figure 5: C3d and NCAM Ig2 stimulation of neurite outgrowth.
Figure 3: Neuritogenic effect of monomeric C3 peptide modified by substitutions (indicated with bold italics) or deletions (indicated by underlining positions of deleted residues).
Figure 4: Mapping of the binding sites of C3m and NCAM Ig2 onto the structure of NCAM Ig1.

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Acknowledgements

The group of the Protein Laboratory was supported by the Danish Biotechnology Programme, The Lundbeck Foundation, the Danish Cancer Society, The Plasmid Foundation, The Danish Growth and Regeneration Programme, and the EU Programme on Biotechnology BIO4-CT96-0450. The group of the Carlsberg Laboratory was supported by the Danish Biotechnology Programme. This is a contribution from the Danish Instrument Center for NMR spectroscopy of Biological Macromolecules. We thank Nils Axelsen, Statens Serum Institut, Copenhagen, Denmark for thoughtful comments during the preparation of the manuscript and Jette Petersen and Charlotte Holm for expert technical assistance.

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Authors and Affiliations

  1. Protein Laboratory, Institute of Molecular Pathology, Panum Institute 6.2, University of Copenhagen, Blegdamsvej 3, Copenhagen N, DK-2200, Denmark

    Lars C.B. Rønn, Marianne Olsen, Vladislav Kiselyov, Vladimir Berezin, Vladislav Soroka & Elisabeth Bock

  2. Chemistry Department, Royal Agricultural and Veterinary University, Thorvaldsensvej 40, Frederiksberg, 1871, Denmark

    Søren Østergaard & Arne Holm

  3. Department of Protein Chemistry, University of Copenhagen, Institute of Molecular Biology, Øster Farimagsgade 2A, Copenhagen, DK-1353, Denmark

    Marie T. Mortensen, Mathilde H. Lerche, Peter H. Jensen & Flemming M. Poulsen

  4. Department of Chemistry, Carlsberg Laboratory, Gamle Carlsberg Vej 10, Valby, DK-2500, Denmark

    Mathilde H. Lerche & Peter H. Jensen

  5. Department of Experimental Pathology, GKT School of Medicine, Guy's Hospital, London, UK

    Jane L. Saffells & Patrick Doherty

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  1. Lars C.B. Rønn
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Correspondence to Lars C.B. Rønn.

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Rønn, L., Olsen, M., Østergaard, S. et al. Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides. Nat Biotechnol 17, 1000–1005 (1999). https://doi.org/10.1038/13697

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