Copper(II) coordination properties of the integrin ligand sequence PHSRN and its new β-cyclodextrin conjugates

Magrı̀, Antonio; D'Alessandro, Franca; Distefano, Donatella A.; Campagna, Tiziana; Pappalardo, Giuseppe; Impellizzeri, Giuseppe; Mendola, Diego La

doi:10.1016/j.jinorgbio.2012.04.002

Cited by 10 publications

(10 citation statements)

References 52 publications

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“…These parameters are similar to those reported for analogous species formed with other acetylated peptides and consistent with a CuN 3 O 1 coordination mode involving one imidazole and two amide deprotonated nitrogen atoms 53. 61–63 The relatively high λ max and ε value, indirectly suggests an involvement of the carboxylate group in binding to Cu 2+ . The EPR parameters (Table 3) indicate an apical interaction in the copper(II) complexes.…”

Section: Resultssupporting

confidence: 85%

Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Travaglia

Mendola

Magrı̀

et al. 2012

Chemistry A European J

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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.

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Section: Resultssupporting

confidence: 85%

Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Travaglia

Mendola

Magrı̀

et al. 2012

Chemistry A European J

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“…are quite similar to the [CuLH −2 ] species obtained for Ac‐PEG‐hIAPP(14–22) ( g || =2.240, A || =168×10 −4 cm −1 ), which are slightly different from those obtained for the PEG‐hIAPP(17–29) ( g || =2.225, A || =161×10 −4 cm −1 ) and rIAPP(17–29)R18H ( g || =2.223, A || =151×10 −4 cm −1 ). In particular, the hyperfine coupling constant is lower for these last two systems and similar to that reported for a peptide with a proline residue located next to the histidine residue at the N‐terminus portion, which is analogous to the prion peptide fragments in which the deprotonation processes occur necessarily toward the C terminus …”

Section: Resultsmentioning

confidence: 99%

“…In particular, the hyperfine coupling constant is lower for these last two systems and similart ot hat reportedf or ap eptidew ith ap roline residue located next to the histidine residue at the N-terminus portion,w hich is analogoust ot he prion peptidef ragments in which the deprotonation processes occur necessarily toward the Cterminus. [74][75][76][77] Speciation unveils the protective role of increasing the Cu 2 + concentrationo nt he hIAPP aggregate formation and the oxi- dative contribution of adventitioust races of Cu 2 + ions on H 2 O 2 production caused by the polypeptide alone.…”

Section: Speciation Stability Constants and Coordination Modes Ofmentioning

confidence: 99%

New Insight in Copper‐Ion Binding to Human Islet Amyloid: The Contribution of Metal‐Complex Speciation To Reveal the Polypeptide Toxicity

Magrı̀

Mendola

Nicoletti

et al. 2016

Chemistry A European J

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Type-2 diabetes (T2D) is considered to be a potential threat on a global level. Recently, T2D has been listed as a misfolding disease, such as Alzheimer's and Parkinson's diseases. Human islet amyloid polypeptide (hIAPP) is a molecule cosecreted in pancreatic β cells and represents the main constituent of an aggregated amyloid found in individuals affected by T2D. The trace-element serum level is significantly influenced during the development of diabetes. In particular, the dys-homeostasis of Cu(2+) ions may adversely affect the course of the disease. Conflicting results have been reported on the protective role played by complex species formed by Cu(2+) ions with hIAPP or its peptide fragments in vitro. The histidine (His) residue at position 18 represents the main binding site for the metal ion, but contrasting results have been reported on other residues involved in metal-ion coordination, in particular those toward the N or C terminus. Sequences that encompass regions 17-29 and 14-22 were used to discriminate between the two models of the hIAPP coordination mode. Due to poor solubility in water, poly(ethylene glycol) (PEG) derivatives were synthesized. A peptide fragment that encompasses the 17-29 region of rat amylin (rIAPP) in which the arginine residue at position 18 was substituted by a histidine residue was also obtained to assess that the PEG moiety does not alter the peptide secondary structure. The complex species formed by Cu(2+) ions with Ac-PEG-hIAPP(17-29)-NH2 , Ac-rIAPP(17-29)R18H-NH2 , and Ac-PEG-hIAPP(14-22)-NH2 were studied by using potentiometric titrations coupled with spectroscopic methods (UV/Vis, circular dichroism, and EPR). The combined thermodynamic and spectroscopic approach allowed us to demonstrate that hIAPP is able to bind Cu(2+) ions starting from the His18 imidazole nitrogen atom toward the N-terminus domain. The stability constants of copper(II) complexes with Ac-PEG-hIAPP(14-22)-NH2 were used to simulate the different experimental conditions under which aggregate formation and oxidative stress of hIAPP has been reported. Speciation unveils: 1) the protective role played by increased amounts of Cu(2+) ions on the hIAPP fibrillary aggregation, 2) the effect of adventitious trace amounts of Cu(2+) ions present in phosphate-buffered saline (PBS), and 3) a reducing fluorogenic probe on H2 O2 production attributed to the polypeptide alone.

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“…Human serum albumin is probably the best known and most studied histidine containing molecule with an outstanding Cu(II) and Ni(II) binding affinity. 279 The (N im ,2N amide ) coordination mode was found to predominate in this case and it was also suggested that a conjugation with cyclodextrins does not affect this coordination mode. The results obtained for this type of interactions for insulin mimetic vanadium complexes 267 and a copper based drug 268 were reported recently.…”

Section: Metal Complexes Of Peptide Fragments Of Prion Proteinmentioning

confidence: 73%

Metal complexes of amino acids and peptides

Farkas¹,

Sóvágó²

2014

Amino Acids, Peptides and Proteins

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Copper(II) coordination properties of the integrin ligand sequence PHSRN and its new β-cyclodextrin conjugates

Cited by 10 publications

References 52 publications

Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Copper, BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

New Insight in Copper‐Ion Binding to Human Islet Amyloid: The Contribution of Metal‐Complex Speciation To Reveal the Polypeptide Toxicity

Metal complexes of amino acids and peptides

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