Abstract
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.
Highlights
The neurotrophins (NTs) are a structurally and functionally related family of growth factors that form non-covalently linked homodimers able to regulate cell survival, differentiation, neurite outgrowth and regeneration, and synaptic plasticity in both the central and the peripheral nervous system [1]
Of thesesynthesized peptides frompeptide a structural and functional point of To view, here we report on mimicking the abilityability of a newly named d-nerve growth factor (NGF)(1-15), point of view, hereform we report on the ability of a newly peptide named which isunits which is the dimeric of NGF(1–14)
Experimental and in silico approaches allowed us to disclose NGF mimetic peptides encompassing the N-terminal domain of the whole protein NGF
Summary
The neurotrophins (NTs) are a structurally and functionally related family of growth factors that form non-covalently linked homodimers able to regulate cell survival, differentiation, neurite outgrowth and regeneration, and synaptic plasticity in both the central and the peripheral nervous system [1]. The biological functions of NTs are tuned through ligand-induced activation of two classes of cell surface receptors—the Trk receptors and the p75 neurotrophin receptor (p75NTR) [3]. The Trk receptors are tyrosine kinase receptors that dimerize upon NTs binding, resulting in autophosphorylation of intracellular tyrosine residues and signal transduction cascade [4]. Among the NTs, the NGF is the first discovered cell growth factor and continues to raise a widespread interest [6]. NGF acts through the binding to a tropomyosin receptors kinase
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