Cells (Apr 2019)

The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides

  • Irina Naletova,
  • Cristina Satriano,
  • Adriana Pietropaolo,
  • Fiorenza Gianì,
  • Giuseppe Pandini,
  • Viviana Triaca,
  • Giuseppina Amadoro,
  • Valentina Latina,
  • Pietro Calissano,
  • Alessio Travaglia,
  • Vincenzo Giuseppe Nicoletti,
  • Diego La Mendola,
  • Enrico Rizzarelli

DOI
https://doi.org/10.3390/cells8040301
Journal volume & issue
Vol. 8, no. 4
p. 301

Abstract

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Nerve growth factor (NGF) is a protein necessary for development and maintenance of the sympathetic and sensory nervous systems. We have previously shown that the NGF N-terminus peptide NGF(1-14) is sufficient to activate TrkA signaling pathways essential for neuronal survival and to induce an increase in brain-derived neurotrophic factor (BDNF) expression. Cu2+ ions played a critical role in the modulation of the biological activity of NGF(1-14). Using computational, spectroscopic, and biochemical techniques, here we report on the ability of a newly synthesized peptide named d-NGF(1-15), which is the dimeric form of NGF(1-14), to interact with TrkA. We found that d-NGF(1-15) interacts with the TrkA-D5 domain and induces the activation of its signaling pathways. Copper binding to d-NGF(1-15) stabilizes the secondary structure of the peptides, suggesting a strengthening of the noncovalent interactions that allow for the molecular recognition of D5 domain of TrkA and the activation of the signaling pathways. Intriguingly, the signaling cascade induced by the NGF peptides ultimately involves cAMP response element-binding protein (CREB) activation and an increase in BDNF protein level, in keeping with our previous result showing an increase of BDNF mRNA. All these promising connections can pave the way for developing interesting novel drugs for neurodegenerative diseases.

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