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Copper(II) interaction with peptide fragments of Histidine-Proline-Rich Glycoprotein: speciation, stability, binding details
No full textGHHPH is the peptide repeat present in histidine–proline rich glycoprotein (HPRG), a plasma glycoprotein involved
in angiogenesis process. The copper(II) ions interaction with mono (Ac-GHHPHG-NH2) and its
bis-repeat (Ac-GHHPHGHHPHG-NH2) was investigated by means of potentiometric and spectroscopic techniques. To single out the copper(II) coordination environments of different species formed with
Ac-GHHPHG-NH2, three single point mutated peptides were also synthesized and their ability to coordinate
Cu2+ investigated. Ac-GHHPHG-NH2 binds Cu2+ by the imidazole side chain and the amide nitrogen deprotonation
that takes place towards the N-terminus. The bis-repeat is able to bind Cu2+ more efficiently than
Ac-GHHPHG-NH2. This difference is not only due to the number of His residues in the sequence but also to
the different binding sites. In fact, the comparison of the potentiometric and spectroscopic data of the
copper(II) complexes with a bis-repeatPeg construct Ac-(GHHPHG)-Peg-(GHHPHG)-NH2 and those of the
metal complexes with Ac-HGHH-NH2, indicates that the central HGHH amino acid sequence is the main
copper(II) binding site
Copper, BDNF and its N-terminal Domain: Inorganic Features and Biological Perspectives
No full textBrain-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
Alzheimers disease. Metal ions may influence the BDNF activity and it is well known that the alteration of
Cu2+ 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 Cu2+ ions has been reported up to now. Cu2+ 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 Cu2+ 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 Cu2+. The effect of metal addition is
opposite to that observed for the analogousfragment of nerve growth factor (NGF) protein, highlighting the role of
specific domains, and suggesting that Cu2+ may drive different pathways for the BDNF and NGF in physiological as
well as pathological conditions
Age-related chances of mitochondrial cytochrome C oxidase and F(0)F(1)-ATP synthase subunit contents in rat cerebral cortex
No full textThe levels of subunits I, II/III, and IV of cytochrome c oxidase and of subunits alpha. beta and gamma of F(0)F(1)-ATP synthase in inner mitochondrial membrane proteins purified from cerebral cortex of rat at 2, 6, 12, 18, 24, 26 months of age were analyzed by Western blot. Age-related changes in the content of subunits, encoded either in mitochondrial or nuclear DNA, were observe
Interactions of Cu2+ with the N-terminus fragment of brain-derived neurotrophic factor encompassing the recognition domain of the TrkB receptor
No full textThe inorganic perspectives of neurotrophins and Alzheimer's disease
No full textThe recent metal hypothesis represents an attempt of a new interpretation key of Alzheimer's disease (AD) to
overcome the limits of amyloid cascade. Neurons need to maintain metal ions within a narrow range of concentrations to avoid a detrimental alteration
of their homeostasis, guaranteed by a network of specific metal ion transporters and chaperones. Indeed,
it is well known that transition metal ions take part in neuromodulation/neurotrasmission. In addition, they are prominent factors in the development and exacerbation of neurodegeneration.
Neurotrophins are proteins involved in development, maintenance, survival and synaptic plasticity of central
and peripheral nervous systems. A neurotrophin hypothesis of AD has been proposed, whereas the link between
neurotrophic factor, the amyloid cascade and biometals has not been taken into account. As a matter of fact, there is a significant overlap between brain areas featured by metal ion dys-homeostasis, and those where the neurotrophins exert their biological activity. Metal ions can directly modulate their activities, through conformational changes, and/or indirectly by activating their downstream signaling in a neurotrophin independent mode.
The focus of this review is on the molecular aspects of Zn2+ and Cu2+ interactions with neurotrophins, with the
aim to shed light on the intricate mechanisms involving metallostasis and proteostasis in AD
Regulation of cytochrome c oxidase and FoF1-ATPase subunits expression in rat brain during aging
No full textIn the present study we analyzed the age-dependent changes of mRNA levels for cytochrome c oxidase and FoF1-ATP synthase subunits in rat cerebral cortex and cerebellum. To establish whether the regulation of expression is transcriptional or post-transcriptional, the results were compared to those related to protein subunits levels, of the same enzymatic complexes, previously observed. The different patterns of age-related changes of mRNA subunits, in particular the lower increments, compared with those related to protein subunits, indicate that post-transcriptional mechanisms of regulation might be involved in the coordinated expression of the various subunits of each complex. Northern blotting analyses of RNA from the cerebellum of rats at the various ages, showed also differences in age-dependent patterns of transcription between cerebral cortex and cerebellum. Moreover, the major age-dependent changes of mitochondrial-encoded subunits, compared with the nuclear-encoded ones, previously observed at proteins level, occur also during transcriptio
Copper(II) interaction with histidine-proline rich glycoprotein fragments and their anti-angiogenic activity
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