The Inorganic Perspective of VEGF: Interactions of Cu2+ with Peptides Encompassing a Recognition Domain of the VEGF Receptor

Grasso, Giulia; Santoro, Anna Maria; Magrı̀, Antonio; Mendola, Diego La; Tomasello, Marianna Flora; Zimbone, Stefania; Rizzarelli, Enrico

doi:10.1016/j.jinorgbio.2016.03.004

Cited by 16 publications

(13 citation statements)

References 72 publications

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“…This combinational approach, employing basic folding principles and incorporating short sequences or key residues from the β-sheet domain, was also reported for β-sheet-forming peptide design [35,36]. We showed that the VEGF73-101 peptide induced endothelial cell death and counteracted the proliferative effect of VEGF165 [34]. In addition, the β-sheet conformation of VEGF73-101 suggested that the peptide could adopt a configuration similar to the antiparallel β-sheet structure of the VEGF165 β5-β6 loop.…”

Section: Introductionmentioning

confidence: 55%

“…To evaluate the importance of the VEGF73-101 peptide structure, we designed two new sequences (VEGFQ79G and VEGFI83G) by replacing two aminoacidic residues in position 79 (Q vs. G) and 83 (I vs. G), respectively. These residues are included in the hydrophobic sequence region of VEGF73-101, and are indicated [34] as crucial for VEGF-VEGFR interactions (for detailed sequences of all peptides included in this study, see Table 1).…”

Section: Peptides: Hydrophobicity and Conformational Analysismentioning

confidence: 99%

“…In our recent work, we reported on the pro-apoptotic activity of the VEGF73-101 peptide, which encompasses the β5-β6 loop of the VEGF165 protein sequence [34]. Specifically, VEGF73-101 combines two amino acid sequences with the following dissimilar characteristics: 73-85 sequence rich in hydrophobic residues and involved in binding with VEGFR2, and 85-101 sequence characterized by the presence of three histidines able to coordinate Cu(II) [23,34]. This combinational approach, employing basic folding principles and incorporating short sequences or key residues from the β-sheet domain, was also reported for β-sheet-forming peptide design [35,36].…”

Section: Introductionmentioning

confidence: 99%

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The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

Zimbone

Santoro

Mendola

et al. 2020

IJMS

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Copper plays an important role as a regulator in many pathologies involving the angiogenesis process. In cancerogenesis, tumor progression, and angiogenic diseases, copper homeostasis is altered. Although many details in the pathways involved are still unknown, some copper-specific ligands have been successfully used as therapeutic agents. Copper-binding peptides able to modulate angiogenesis represent a possible way to value new drugs. We previously reported that a fragment (VEGF73-101) of vascular endothelial growth factor (VEGF165), a potent angiogenic, induced an apoptotic effect on human umbilical vein endothelial cells. The aim of this study was to investigate the putative copper ionophoric activity of VEGF73-101, as well as establish a relationship between the structure of the peptide fragment and the cytotoxic activity in the presence of copper(II) ions. Here, we studied the stoichiometry and the conformation of the VEGF73-101/Cu(II) complexes and some of its mutated peptides by electrospray ionization mass spectrometry and circular dichroism spectroscopy. Furthermore, we evaluated the effect of all peptides in the absence and presence of copper ions by cell viability and cytofuorimetric assays. The obtained results suggest that VEGF73-101 could be considered an interesting candidate in the development of new molecules with ionophoric properties as agents in antiangiogenic therapeutic approaches.

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Section: Introductionmentioning

confidence: 55%

Section: Peptides: Hydrophobicity and Conformational Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

Zimbone

Santoro

Mendola

et al. 2020

IJMS

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“…This binding leads to the release of caspase 3, which triggers XIAP-mediated apoptosis [ 45 , 46 ]. Copper performs a number of important functions, including the following: taking part in the Ras/MAP-kinase (Ras/Mitogen-activated protein kinase) [ 47 ] and Raf of murine oncogene sarcoma homologue B1-dependent [ 48 ] signaling pathways; modulating the function of growth factor receptors [ 49 , 50 ], γ-aminobutyric acid [ 51 ], and glutamate receptors [ 52 ]; regulating cyclic-AMP-dependent lipolysis [ 53 ]; and inducing Golgi-complex independent secretion of interleukins and cytokines [ 54 ]. It has also been shown that copper controls organogenesis and cell differentiation in embryo development [ 55 ].…”

Section: Biological Roles Of Coppermentioning

confidence: 99%

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin as a Nutritive Source of Copper: Overview of the Current Data

et al. 2018

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Copper, which can potentially be a highly toxic agent, is an essential nutrient due to its role as a cofactor for cuproenzymes and its participation in signaling pathways. In mammals, the liver is a central organ that controls copper turnover throughout the body, including copper absorption, distribution, and excretion. In ontogenesis, there are two types of copper metabolism, embryonic and adult, which maintain the balance of copper in each of these periods of life, respectively. In the liver cells, these types of metabolism are characterized by the specific expression patterns and activity levels of the genes encoding ceruloplasmin, which is the main extracellular ferroxidase and copper transporter, and the proteins mediating ceruloplasmin metalation. In newborns, the molecular genetic mechanisms responsible for copper homeostasis and the ontogenetic switch from embryonic to adult copper metabolism are highly adapted to milk ceruloplasmin as a dietary source of copper. In the mammary gland cells, the level of ceruloplasmin gene expression and the alternative splicing of its pre-mRNA govern the amount of ceruloplasmin in the milk, and thus, the amount of copper absorbed by a newborn is controlled. In newborns, the absorption, distribution, and accumulation of copper are adapted to milk ceruloplasmin. If newborns are not breast-fed in the early stages of postnatal development, they do not have this natural control ensuring alimentary copper balance in the body. Although there is still much to be learned about the neonatal consequences of having an imbalance of copper in the mother/newborn system, the time to pay attention to this problem has arrived because the neonatal misbalance of copper may provoke the development of copper-related disorders.

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“…This binding leads to the release of caspase 3, which triggers XIAP-mediated apoptosis [40,41]. Copper also takes part in the Ras/MAP-kinase [42] and BRAF-dependent [43] signaling pathways, modulates the function of growth factor receptors [44,45], γ-aminobutyric acid [46] and glutamate receptors [47], regulates cyclic-AMP-dependent lipolysis [48], and induces Golgi-complex independent secretion of interleukins and cytokines [49]. It has been…”

Section: Mitochondrial Inner Membranementioning

confidence: 99%

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin As a Nutritive Source of Copper

Puchkova¹,

Babich²,

Zatulovskaia³

et al. 2018

Preprint

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Copper, which can potentially be a highly toxic agent, is an essential nutrient due to its role as a co-factor for cuproenzymes and participation in signaling pathways. In mammals, the liver is a central organ that controls copper turnover throughout the body: copper absorption, distribution, and excretion. In ontogenesis, there are two types of copper metabolism: embryonic and adult, which maintain the balance of copper in each of these periods, respectively. In the liver cells, these types are characterized by specific expression patterns and activity levels of the genes encoding ceruloplasmin, which is the main extracellular ferroxidase and copper transporter and proteins mediating ceruloplasmin metalation. In newborns, the molecular-genetic mechanisms responsible for copper homeostasis and the ontogenetic switch from embryonic to adult copper metabolism are highly adapted to milk ceruloplasmin as a dietary source of copper. In the mammary gland cells, the level of ceruloplasmin gene expression and the alternative splicing of its pre-mRNA govern the amount of ceruloplasmin in milk, and thus, the amount of copper absorbed by the newborn is controlled. In the newborns, absorption, distribution, and accumulation copper are adapted to milk ceruloplasmin. In the newborns, which are not breast-fed at the early stages of postnatal development, the control for alimentary copper balance is absent. We tried to focus on the neonatal consequences of a violation of the balance of copper in the mother / newborn system. Although there is still much to be learned, the time to pay attention to this problem came because the neonatal misbalance of copper may provoke the development of copper related disorders for future life.

show abstract

The Inorganic Perspective of VEGF: Interactions of Cu2+ with Peptides Encompassing a Recognition Domain of the VEGF Receptor

Cited by 16 publications

References 72 publications

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin as a Nutritive Source of Copper: Overview of the Current Data

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin As a Nutritive Source of Copper

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