PMID- 30939824 OWN - NLM STAT- MEDLINE DCOM- 20191127 LR - 20231011 IS - 2073-4409 (Print) IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 8 IP - 4 DP - 2019 Apr 1 TI - The Copper(II)-Assisted Connection between NGF and BDNF by Means of Nerve Growth Factor-Mimicking Short Peptides. LID - 10.3390/cells8040301 [doi] LID - 301 AB - 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. Cu(2+) 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. FAU - Naletova, Irina AU - Naletova I AD - Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. irina_naletova@yahoo.com. FAU - Satriano, Cristina AU - Satriano C AUID- ORCID: 0000-0001-5348-5863 AD - Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. csatriano@unict.it. FAU - Pietropaolo, Adriana AU - Pietropaolo A AD - Department of Health Sciences, University of Catanzaro, Campus Universitario Viale Europa, 88100 Catanzaro, Italy. apietropaolo@unicz.it. FAU - Giani, Fiorenza AU - Giani F AUID- ORCID: 0000-0002-1901-8230 AD - Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, via Palermo n. 636, 95122 Catania, Italy. fiorenza.giani@gmail.com. FAU - Pandini, Giuseppe AU - Pandini G AD - Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, via Palermo n. 636, 95122 Catania, Italy. gpandini@gmail.com. FAU - Triaca, Viviana AU - Triaca V AD - Medicina Molecolare e Traslazionale "Rita Levi Montalcini", Institute of Cellular Biology and Neurobiology (IBCN), National Research Council (CNR), c/o Policlinico Umberto I, University of Rome "La Sapienza", Via del Policlinico 255, 00161 Rome, Italy. vtriaca75@gmail.com. FAU - Amadoro, Giuseppina AU - Amadoro G AD - Institute of Translational Pharmacology (IFT), National Research Council (CNR), 00131 Rome, Italy. giusy.amadoro@gmail.com. FAU - Latina, Valentina AU - Latina V AD - European Brain Research Institute, Viale Regina Elena 295, 00161, 64-65, 00143 Rome, Italy. valentina.latina@libero.it. FAU - Calissano, Pietro AU - Calissano P AD - European Brain Research Institute, Viale Regina Elena 295, 00161, 64-65, 00143 Rome, Italy. pietro.calissano@gmail.com. FAU - Travaglia, Alessio AU - Travaglia A AD - Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. alessio_travaglia@hotmail.it. FAU - Nicoletti, Vincenzo Giuseppe AU - Nicoletti VG AD - Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95124 Catania, Italy. nicovigi@unict.it. FAU - La Mendola, Diego AU - La Mendola D AUID- ORCID: 0000-0002-4193-7612 AD - Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy. lamendola@farm.unipi.it. FAU - Rizzarelli, Enrico AU - Rizzarelli E AD - Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy. erizzarelli@unict.it. AD - Institute of Crystallography-Catania, National Research Council (CNR), Via P. Gaifami, 95126 Catania, Italy. erizzarelli@unict.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190401 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Ionophores) RN - 789U1901C5 (Copper) RN - 9061-61-4 (Nerve Growth Factor) RN - EC 2.7.10.1 (Receptor, trkA) SB - IM MH - Amino Acid Sequence MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cell Differentiation/drug effects MH - Cell Proliferation/drug effects MH - Cell Shape/drug effects MH - Copper/*pharmacology MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Dimerization MH - Endocytosis/drug effects MH - Female MH - Ionophores/pharmacology MH - Nerve Growth Factor/chemistry/*metabolism MH - PC12 Cells MH - Phenotype MH - Phosphorylation/drug effects MH - Protein Domains MH - Rats MH - Rats, Wistar MH - Receptor, trkA/chemistry/metabolism MH - Thermodynamics PMC - PMC6523629 OTO - NOTNLM OT - Alzheimer's disease OT - CREB OT - TrK OT - brain derived neurotrophic factor OT - copper OT - metal ions OT - nerve growth factor OT - neurotrophin OT - p75 OT - synapsin COIS- The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. EDAT- 2019/04/04 06:00 MHDA- 2019/04/04 06:01 PMCR- 2019/04/01 CRDT- 2019/04/04 06:00 PHST- 2019/03/04 00:00 [received] PHST- 2019/03/23 00:00 [revised] PHST- 2019/03/30 00:00 [accepted] PHST- 2019/04/04 06:00 [entrez] PHST- 2019/04/04 06:00 [pubmed] PHST- 2019/04/04 06:01 [medline] PHST- 2019/04/01 00:00 [pmc-release] AID - cells8040301 [pii] AID - cells-08-00301 [pii] AID - 10.3390/cells8040301 [doi] PST - epublish SO - Cells. 2019 Apr 1;8(4):301. doi: 10.3390/cells8040301.