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NCAM Mimetic Peptides: An Update

  • Vladimir BerezinEmail author
  • Elisabeth Bock
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 663)

Abstract

The neural cell adhesion molecule (NCAM) is involved in multiple, relatively low affinity interactions with itself and with other cell surface receptors and growth factors. Its cytoplasmic domains do not posses any intrinsic enzymatic activity, which makes it difficult to develop reliable pharmacological tools interfering with NCAM functions. Recent progress in our understanding of the structural basis of NCAM-mediated cell adhesion and signaling has allowed a structure-based design of NCAM mimetic peptides. Using this approach, a number of peptides termed P2, P1-B, P-3-DE and P-3-G, whose sequences contain one or several NCAM homophilic binding sites involved in NCAM binding to itself, have been identified. By means of NMR titration analysis and molecular modeling, a number of peptides derived from NCAM and targeting NCAM heterophilic ligands, such as the fibroblast growth factor receptor and heparan sulfate proteoglycans, (HSPG) have been identified. The FGL, dekaCAM, FRM/EncaminA, BCL, EncaminC and EncaminE peptides, all target the FGF receptor, whereas the heparin-binding peptide HBP targets HSPG. Moreover, a number of NCAM-binding peptides have been identified employing screening of combinatorial peptide libraries. The C3 and NBP10 peptides target the first Ig module, whereas the ENFIN2 and ENFIN11 peptides target fibronectin type III (FN3) modules of NCAM. A number of NCAM mimetics can induce neurite outgrowth and exhibit neuroprotective and synaptic plasticity modulating properties in vitro and in vivo, making them attractive pharmacological tools suitable for drug development for the treatment of neurodegenerative disorders and impaired memory.

Keywords

Cell adhesion NCAM Mimetic peptides Neurodegenerative disorders Learning and memory 

References

  1. 1.
    Walmod PS, Pedersen MV, Berezin V, Bock E (2007) Chapter 2: cell adhesion molecules of the immunoglobulin superfamily in the nervous system. In: Lajtha) A (ed) Handbook of neurochemistry and molecular neurobiology. Vol. 7: neural protein metabolism and function. Springer, New York, USA, pp 35-151Google Scholar
  2. 2.
    Kiryushko D, Bock E, Berezin V (2007) Pharmacology of cell adhesion molecules of the nervous system. Curr Neuropharmacol 5:253-267PubMedCrossRefGoogle Scholar
  3. 3.
    Berezin V, Bock E (2004) NCAM mimetic peptides: pharmacological and therapeutic potential. J Mol Neurosci 22:33-40PubMedCrossRefGoogle Scholar
  4. 4.
    Soroka V, Kolkova K, Kastrup JS et al (2003) Structure and interactions of NCAM Ig-1-2-3 suggest a novel zipper mechanisms for homophilic adhesion. Structure 11:1291-1301PubMedCrossRefGoogle Scholar
  5. 5.
    Kiselyov VV, Soroka V, Berezin V, Bock E (2005) Structural biology of NCAM homophilic binding and activation of FGFR. J Neurochem 94:1169-1179PubMedCrossRefGoogle Scholar
  6. 6.
    Heiland PC, Griffith LS, Lange R et al (1998) Tyrosine and serine phosphorylation of the neural cell adhesion molecule L1 is implicated in its oligomannosidic glycan dependent association with NCAM and neurite outgrowth. Eur J Cell Biol 75:97-106PubMedGoogle Scholar
  7. 7.
    Milev P, Maurel P, Haring M et al (1996) TAF-1/axonin-1 is a high-affinity ligand of neurocan, phosphacan/protein-tyrosine phosphatase-zeta/beta, and N-CAM. J Biol Chem 271:15716-15723PubMedCrossRefGoogle Scholar
  8. 8.
    Dzhandzhugazyan K, Bock E (1997) demonstration of an extracellular ATP-binding site in NCAM: functional implications of nucleotide binding. Biochemistry 36:15381-15395PubMedCrossRefGoogle Scholar
  9. 9.
    Kiselyov V, Skladchikova G, Hinsby AM et al (2003) Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure 11:691-701PubMedCrossRefGoogle Scholar
  10. 10.
    Paratcha G, Ledda F, Ibáñez CF (2003) The neural cell adhesion molecule NCAM is an alternative signaling receptor for GDBF family ligands. Cell 113:867-879PubMedCrossRefGoogle Scholar
  11. 11.
    Cole GJ, Schubert D, Glaser L (1985) Cell-substratum adhesion in chick neural retina depends upon protein-heparan sulfate interactions. J Cell Biol 100:1192-1199PubMedCrossRefGoogle Scholar
  12. 12.
    Nybroe O, Moran N, Bock E (1989) Equilibrium binding analysis of neural cell adhesion molecule binding to heparin. J Neurochem 52:1947-1949PubMedCrossRefGoogle Scholar
  13. 13.
    Herndon ME, Stipp CS, Lander AD (1999) Interactions of neural glycosaminoglycans and proteoglycans with protein ligands: assessment of selectivity heterogeneity and the participation of core proteins in binding. Glycobiology 9:143-155PubMedCrossRefGoogle Scholar
  14. 14.
    Probstmeier R, Kuhn K, Schachner M (1989) Binding properties of the neural cell adhesion molecule to different components of the extracellular matrix. J Neurochem 53:1794-1801PubMedCrossRefGoogle Scholar
  15. 15.
    Thoulouze M-I, Lagafe M, Schachner M et al (1998) The neural cell adhesion molecule is a receptor for rabies virus. J Virol 72:7181-7190PubMedGoogle Scholar
  16. 16.
    Schmitt-Ulms G, Legname G, Baldwin MA et al (2001) Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J Mol Biol 314:1209-1225PubMedCrossRefGoogle Scholar
  17. 17.
    Rønn LC, Olsen M, Ostergaard S et al (1999) Identification of a neuritogenic ligand of the neural cell adhesion molecule using a combinatorial library of synthetic peptides. Nat Biotechnol 17:1000-1005PubMedCrossRefGoogle Scholar
  18. 18.
    Jensen PH, Soroka V, Thomsen NK et al (1999) Structure and interactions of NCAM modules 1 and 2 - basic elements in neural cell adhesion. Nat Struct Biol 6:486-493PubMedCrossRefGoogle Scholar
  19. 19.
    Rønn LC, Doherty P, Holm A et al (2000) Neurite outgrowth induced by a synthetic peptide ligand of NCAM requires fibroblast growth factor receptor activation. J Neurochem 75:665-671PubMedCrossRefGoogle Scholar
  20. 20.
    Kolkova K, Novitskaya V, Pedersen N et al (2000) Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway. J Neurosci 20:2238-2246PubMedGoogle Scholar
  21. 21.
    Jessen U, Novitskaya V, Pedersen N et al (2001) The transcription factors CREB and c-Fos play key roles in NCAM-mediated neuritogenesis in PC12-E2 cells. J Neurochem 79:1149-1160PubMedCrossRefGoogle Scholar
  22. 22.
    Ditlevsen DK, Køhler LB, Pedersen MV et al (2003) The role of phosphatidylinositol 3-kinase in neural cell adhesion molecule-mediated neuronal differentiation and survival. J Neurochem 84:546-556PubMedCrossRefGoogle Scholar
  23. 23.
    Ditlevsen DK, Berezin V, Bock E (2007) Signalling pathways underlying neural cell adhesion molecule-mediated survival of dopaminergic neurons. Eur J NeuroSci 6:1678-1684CrossRefGoogle Scholar
  24. 24.
    Ditlevsen DK, Køhler LB, Berezin V, Bock E (2007) Cyclic guanosine monophosphate signalling pathway plays a role in neural cell adhesion molecule-mediated neurite outgrowth and survival. J Neurosci Res 85:703-711PubMedCrossRefGoogle Scholar
  25. 25.
    Kiryushko D, Kofoed T, Skladchikova D (2003) A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons. J Biol Chem 278:12325-12334PubMedCrossRefGoogle Scholar
  26. 26.
    Seidenfaden R, Krauter A, Schertzinger F et al (2003) Polysialic acid directs tumor cell growth by controlling heterophilic neural cell adhesion molecule interactions. Mol Cell Biol 23:5908-5918PubMedCrossRefGoogle Scholar
  27. 27.
    Klementiev B, Bichevaja N, Novikova T et al (2002) A peptide agonist of the neural cell adhesion molecule (NCAM), C3, protects against developmental defects induced by a teratogen pyrimethamine. Int J Dev Neurosci 20:527-536PubMedCrossRefGoogle Scholar
  28. 28.
    Folly AG, Hartz BP, Gallagher HC et al (2000) A synthetic peptide ligand of neural cell adhesion molecule (NCAM) IgI domain prevents NCAM internalization and disrupts passive avoidance learning. J Neurochem 74:2807-2813Google Scholar
  29. 29.
    Hartz BP, Sohoel A, Berezin V et al (2003) A synthetic peptide ligand of NCAM affects exploratory behavior and memory in rodents. Pharmacol Biochem Behav 75:861-867PubMedCrossRefGoogle Scholar
  30. 30.
    Cambon K, Venero C, Berezin V et al (2003) Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning. Neuroscience 122:183-191PubMedCrossRefGoogle Scholar
  31. 31.
    Sakai A, Asado M, Seno N, Suzuki H (2008) Involvement of neural cell adhesion molecule signaling in glial cell line-derived neurotrophic factor-induced analgesia in a rat model of neuropathic pain. Pain 137:378-388Google Scholar
  32. 32.
    Rønn LC, Olsen M, Soroka V et al (2002) Characterization of a novel NCAM ligand with a stimulatory effect on neurite outgrowth identified by screening a combinatorial peptide library. Eur J NeuroSci 16:1720-1730PubMedCrossRefGoogle Scholar
  33. 33.
    Hansen RK, Christensen C, Korshunova I et al (2007) Identification of NCAM-binding peptides promoting neurite outgrowth via a heterotrimeric G-protein-coupled pathway. J Neurochem 103:1396-1407PubMedCrossRefGoogle Scholar
  34. 34.
    Kasper C, Rasmussen H, Kastrup JS et al (2000) Structural basis of cell-cell adhesion by NCAM. Nat Struct Biol 7:389-393PubMedCrossRefGoogle Scholar
  35. 35.
    Soroka V, Kiryushko D, Novitskaya V et al (2002) Induction of neuronal differentiation by a peptide corresponding to the homophilic binding site of the second Ig module of the neural cell adhesion molecule. J Biol Chem 277:24676-24683PubMedCrossRefGoogle Scholar
  36. 36.
    Kiryushko D, Korshunova I, Berezin V, Bock E (2006) Neural cell adhesion molecule induces intracellular signaling via multiple mechanisms of Ca2+ homeostasis. Mol Biol Cell 17:2278-2286PubMedCrossRefGoogle Scholar
  37. 37.
    Li S, Kolkova K, Rudenko O et al (2005) Triple effect of mimetic peptides interfering with neural cell adhesion molecule homophilic cis interactions. Biochemistry 44:5034-5040PubMedCrossRefGoogle Scholar
  38. 38.
    Pedersen MV, Køhler LB, Ditlevsen DK et al (2004) Neuritogenic and survival-promoting effects of the P2-peptide derived from a homophilic binding site in NCAM. J Neurosci Res 75:55-65PubMedCrossRefGoogle Scholar
  39. 39.
    Rizhova L, Klementiev B, Cambon K et al (2007) Effects of P2, a peptide derived from a homophilic binding site in NCAM, on learning and memory in rats. Neuroscience 149:931-942PubMedCrossRefGoogle Scholar
  40. 40.
    Klementiev B, Novikova T, Korshunova I et al (2008) The NCAM-derived P2 peptide facilitates recovery of cognitive and motor function and ameliorates neuropathology following traumatic brain injury. Eur J NeuroSci 27(11):2885-2896PubMedCrossRefGoogle Scholar
  41. 41.
    Walmod PS, Kolkova K, Berezin V, Bock E (2004) Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 29:2015-2035PubMedCrossRefGoogle Scholar
  42. 42.
    Kiselyov VV, Skladchikova G, Hinsby AM et al (2003) Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure 11:691-701PubMedCrossRefGoogle Scholar
  43. 43.
    Christensen C, Lauridsen JB, Berezin V et al (2006) The neural cell adhesion molecule binds to fibroblast growth factor 2. FEBS Lett 580:3386-3390PubMedCrossRefGoogle Scholar
  44. 44.
    Neiiendam JL, Kohler LB, Christensen C et al (2004) An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons. J Neurochem 91:920-935PubMedCrossRefGoogle Scholar
  45. 45.
    Skibo GG, Lushnikova IV, Voronin KY et al (2005) A synthetic NCAM-derived peptide, FGL, protects hippocampal neurons from ischemic insult both in vitro and in vivo. Eur J NeuroSci 22:1589-1596PubMedCrossRefGoogle Scholar
  46. 46.
    Cambon K, Hansen SM, Venero C et al (2004) A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. J Neurosci 24:4197-4204PubMedCrossRefGoogle Scholar
  47. 47.
    Downer EJ, Cowley TR, Lyons A et al. The NCAM-derived peptide, FGL, exerts anti-inflammatory effects in the hippocampus of the aged rats. Neurobiol Aging, in press.Google Scholar
  48. 48.
    Klementiev B, Novikova T, Novitskaya V et al (2007) A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Aβ25-35. Neuroscience 145:209-224PubMedCrossRefGoogle Scholar
  49. 49.
    Secher T, Novitskaia V, Berezin V et al (2006) A neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention. Neuroscience 141:1289-1299PubMedCrossRefGoogle Scholar
  50. 50.
    Popov VI, Medvedev NI, Kraev IV et al (2008) A cell adhesion molecule mimetic, FGL peptide, induces alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats: a three-dimensional ultrastructural study. Eur J NeuroSci 27:301-314PubMedCrossRefGoogle Scholar
  51. 51.
    Borcel E, Perez-Alvarez L, Herrero AI et al (2008) Chronic stress in adulthood followed by intermittent stress impairs spatial memory and survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule. Behavioral Pharmacol 19:41-49CrossRefGoogle Scholar
  52. 52.
    Anand R, Seiberling M, Kamtchoua T, Pokorny R (2007) Tolerability, safety and pharmacokinetics of the FGLL peptide, a novel mimetic of neural cell adhesion molecule, following intranasal administration in healthy volunteers. Clin Pharmacokinet 46:351-358PubMedCrossRefGoogle Scholar
  53. 53.
    Anderson AA, Kendal CE, Garcia-Maya M et al (2005) A peptide from the first fibronectin domain of NCAM acts as an inverse agonist and stimulates FGF receptor activation, neurite outgrowth and survival. J Neurochem 95:570-583PubMedCrossRefGoogle Scholar
  54. 54.
    Carafoli F, Saffell JL, Hohenester E (2008) Structure of the tandem fibronectin type 3 domain of neural cell adhesion molecule. J Mol Biol 377:524-534PubMedCrossRefGoogle Scholar
  55. 55.
    Li S, Christensen C, Kiselyov VV et al (2007) FGF-derived peptides: Functional agonists of the fibroblast growth factor receptor (FGFR). J Neurochem 104:667-682Google Scholar
  56. 56.
    Jacobsen J, Kiselyov VV, Bock E, Berezin V (2008) A peptide motif from the second fibronectin module of the neural cell adhesion molecule NCAM, NLIKQDDGGSPIRHY is a binding site for the FGF-receptor. Neurochem Res 33:2532-2539PubMedGoogle Scholar
  57. 57.
    Hansen SMM, Køhler LB, Li S et al (2008) NCAM-derived peptides function as agonists for the fibroblast growth factor receptor. J Neurochem 106(5):2030-2041PubMedGoogle Scholar
  58. 58.
    Storms SD, Kim AC, Tran BH et al (1996) NCAM-mediated adhesion of transfected cells to agrin. Cell Adhes Commun 3:497-509PubMedCrossRefGoogle Scholar
  59. 59.
    Herndon ME, Sripp CS, Lander AD (1999) Interactions of neural glycosaminoglycans and proteoglycans with protein ligands: assessment of selectivity, heterogeneity and the participation of core proteins in binding. Glycobiology 9:143-155PubMedCrossRefGoogle Scholar
  60. 60.
    Kulahin N, Rudenko O, Kiselyov VV et al (2005) Modulation of the homophilic interaction between the first and second Ig modules of neural cell adhesion molecule by heparin. J Neurochem 95:46-55PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Protein Laboratory, Department of Neuroscience and PharmacologyUniversity of Copenhagen, Panum Institute 24.2Copenhagen NDenmark

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