Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides.
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.
Rønn
L C
LC
Protein Laboratory, Institute of Molecular Pathology, Panum Institute 6.2, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen N, Denmark. lcr@plab.ku.dk
Olsen
M
M
Ostergaard
S
S
Kiselyov
V
V
Berezin
V
V
Mortensen
M T
MT
Lerche
M H
MH
Jensen
P H
PH
Soroka
V
V
Saffell
J L
JL
Doherty
P
P
Poulsen
F M
FM
Bock
E
E
Holm
A
A
Saffells
J L
JL
D000595:Amino Acid Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D020650:Combinatorial Chemistry Techniques; D016384:Consensus Sequence; D007136:Immunoglobulins / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism*; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
D015816:Cell Adhesion Molecules, Neuronal; D007136:Immunoglobulins; D008024:Ligands; D019151:Peptide Library; D010455:Peptides