title: Copper, BDNF and Its N-terminal domain: inorganic features and biological perspectives.
abstract: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer's disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu(2+) homeostasis is a prominent factor in the development of neurological pathologies. The N-terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu(2+) ions has been reported up to now. Cu(2+) complexes of the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of N-terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT-geometry optimizations. Coordination features of the acetylated form, Ac-BDNF(1-12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1-12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu(2+) coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1-12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu(2+). The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu(2+) may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions.
authors.affiliation: Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Travaglia
authors.forename: Diego
authors.initials: D
authors.lastname: La Mendola
authors.forename: Antonio
authors.initials: A
authors.lastname: Magrì
authors.forename: Vincenzo Giuseppe
authors.initials: VG
authors.lastname: Nicoletti
authors.forename: Adriana
authors.initials: A
authors.lastname: Pietropaolo
authors.forename: Enrico
authors.initials: E
authors.lastname: Rizzarelli
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D020932:Nerve Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D010446:Peptide Fragments; D003300:Copper; D020932:Nerve Growth Factor