Arkadius Bonna

CambCol Laboratories Ltd

Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron-regulatory hormone, is a 25-amino-acid peptide with four intramolecular disulfide bonds circulating in blood. Its hormonal activity is indirect and consists of marking ferroportin-1 (an iron exporter) for degradation. Hepcidin biosynthesis involves the N-terminally extended precursors prepro-hepcidin an...

[This corrects the article DOI: 10.3389/fmolb.2022.828674.].

Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron regulatory hormone is a 25 amino acid peptide with 4 intramolecular disulfide bonds, circulating in blood. Its hormonal activity is indirect and consists of marking ferroportin-1 (an iron exporter) for degradation. Hepcidin biosynthesis involves N-terminally extended precursors prepro-hepcidin and pro-h...

Nickel is toxic to humans. Its compounds are carcinogenic. Furthermore, nickel allergy is a severe health problem that affects approximately 10–20% of humans. The mechanism by which these conditions develop remains unclear, but it may involve the cleavage of specific proteins by nickel ions. Ni(II) ions cleave the peptide bond preceding the Ser/Thr...

Type I collagen is the most abundant structural protein in the body and, with other fibrillar collagens, forms the fibrous network of the extracellular matrix (ECM). Another group of ECM polymers, the glycosaminoglycans (GAGs) and GAG-modified proteoglycans, play important roles in regulating collagen behaviors and contribute to the compositional,...

Deficiency in a principal epidermal barrier protein, filaggrin (FLG), is associated with multiple allergic manifestations, including atopic dermatitis and contact allergy to nickel. Toxicity caused by dermal and respiratory exposures of the general population to nickel-containing objects and particles is a deleterious side effect of modern technolo...

Dermatopontin (DPT), a small extracellular matrix protein that stimulates collagen fibrillogenesis, contains sulfotyrosine residues but neither its level of sulfation nor its binding sites on fibrillar collagens are known. Here, we discovered that DPT is present in a relatively high mass concentration (~ 0.02%) in porcine corneal stroma, from which...

Objectives Platelet activation underpins thrombus formation in ischemic stroke. The active, dimeric form of platelet receptor glycoprotein (GP) VI plays key roles by binding platelet ligands collagen and fibrin, leading to platelet activation. We investigated whether patients presenting with stroke expressed more GPVI on their platelet surface and...

Silver-based materials are widely used in clinical medicine. Furthermore, the usage of silver containing materials and devices is widely recommended and clinically approved. The impact on human health of the increasing use of silver nanoparticles in medical devices remains understudied, even though Ag-containing dressings are known to release silve...

Objective GPVI (glycoprotein VI) is a key molecular player in collagen-induced platelet signaling and aggregation. Recent evidence indicates that it also plays important role in platelet aggregation and thrombus growth through interaction with fibrin(ogen). However, there are discrepancies in the literature regarding whether the monomeric or dimeri...

Background Multimerin 1 (human: MMRN1, mouse: Mmrn1) is a homopolymeric, adhesive, platelet and endothelial protein that binds to von Willebrand factor and enhances platelet adhesion to fibrillar collagen ex vivo. Objectives To examine the impact of Mmrn1 deficiency on platelet adhesive function, and the molecular motifs in fibrillar collagen that...

Background and purpose: R5421 has been used as a scramblase inhibitor to determine the role of phospholipid scrambling across a range of systems including platelet procoagulant activity. The selectivity of R5421 has not been thoroughly studied. Here we characterised the effects of R5421 on platelet function and its suitability for use as a scrambl...

NiO nanoparticles and non-stoichiometric black NiO were shown to be effective sources of Ni ²⁺ ions causing sequence-selective peptide bond hydrolysis. NiO nanoparticles were as effective in this reaction as their...

Nickel is harmful to humans, being both carcinogenic and allergenic. However, the mechanisms of this toxicity are still unresolved. We propose that Ni(II) ions disintegrate proteins by hydrolysis of peptide bonds preceding the Ser/Thr−Xaa−His sequences. Such sequences occur in nuclear localization signals (NLSs) of human phospholipid scramblase 1,...

Model peptides relevant to hCtr1 transchelate Cu I from the anti-tumour [CuI(PTA) 4 ] ⁺ complex before metal internalization into tumor cells. ESI(+)MS experiments corroborated by DFT calculations indicate that tetracoordinated-Cu II and linear-Cu I arrangements...

Tissue factor (TF) plays a central role in haemostasis and thrombosis. Following vascular damage, vessel wall TF initiates the extrinsic coagulation cascade. TF can also be exposed by monocytes. Inflammatory or infectious stimuli trigger synthesis of new TF protein by monocytes over the course of hours. It has also been suggested that monocytes can...

Citalopram, a selective serotonin reuptake inhibitor (SSRI), inhibits platelet function in vitro. We have previously shown that this action is independent of citalopram's ability to block serotonin uptake by the serotonin transporter and must therefore be mediated via distinct pharmacological mechanisms. We now report evidence for two novel and put...

Fibrillar collagens of the extracellular matrix are critical for tissue structure and physiology; however, excessive or abnormal deposition of collagens is a defining feature of fibrosis. Regulatory mechanisms that act on collagen fibril assembly potentially offer new targets for antifibrotic treatments. Tissue weakening, altered collagen fibril mo...

Copper Transporter 1 (CTR1) is a homotrimeric membrane protein providing the main route of copper transport into eukaryotic cells from the extracellular milieu. Its N-terminal extracellular domain, rich in His and Met residues, is considered responsible for directing copper into the transmembrane channel. Most of vertebrate CTR1 proteins contain th...

"Multimerin-1 (MMRN1) is a homopolymeric glycoprotein stored in platelets and vascular endothelial cells for regulated release that enhances platelet adhesion to collagen. We tested Mmrn1 contributions to platelet adhesion ex vivo and in vivo using selective deficient mice and triple-helical collagen mimetic peptides to evaluate a putative Mmrn1-se...

Background: Platelet collagen receptor GPVI binds collagen, initiating thrombogenesis and stabilizes thrombi by binding fibrin. Objectives: To determine if GPVI-dimer, monomer, or both bind to fibrinogen substrates, and which region common to these substrates contains the interaction site METHODS: Recombinant GPVI monomeric extracellular domain...

Sequences of the LRRs in (A) fibromodulin and (B) chondroadherin. The colouring scheme of the cap structures is the same as in Fig. 1. The LRR consensus is highlighted in red and the repeat length indicated in the last column.

Fibrin has recently been shown to activate platelets through the immunoglobulin receptor glycoprotein VI (GPVI). In the present study, we show that spreading of human platelets on fibrin is abolished in patients deficient in GPVI, confirming that fibrin activates human platelets through the immunoglobulin receptor. Using a series of proteolytic fra...

Copper(II) complexes of peptides containing a histidine (His) residue at the third position (known as ATCUN or NTS motif) gain interest for their biological roles and biotechnological applications. We characterized three such peptides, Ala-Ala-His-NH2 (AAHam), Ala-βAla-His-NH2 (ABH-am) and βAla-Ala-His-NH2 (BAH-am) by cyclic voltammetry in order to...

The small leucine-rich proteoglycans (SLRPs) are important regulators of extracellular matrix assembly and cell signalling. We have determined crystal structures at ~2.2 Å resolution of human fibromodulin and chondroadherin, two collagen-binding SLRPs. Their overall fold is similar to that of the prototypical SLRP, decorin, but unlike decorin neith...

The intermediate filament protein keratin 8 (K8) interacts with the nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane regulator (CFTR) with phenylalanine 508 deletion (ΔF508), and this interaction hampers the biogenesis of functional ΔF508-CFTR and its insertion into the plasma membrane. Interruption of this interaction may co...

Copper complexes of metal binding domains of synthesized amyloid-β peptides – Aβ(1-16) and N-truncated Aβ(4-16) containing a novel N-terminal FRH sequence, as well as its shorter mutants were characterized by cyclic voltammetry. The influence of the peptide sequence and peptide to copper molar ratio on the electrochemical properties of the obtained...

The influence of cation-π interactions on the electrochemical properties of copper(II) complexes with synthesized pentapeptide C-terminal fragment of Atrial Natriuretic Factor (ANF) hormone was studied in this work. Molecular modeling performed for Cu(II)-NSFRY-NH2 complex indicated that the cation-π interactions between Tyr and Cu(II), and also be...

α-Factor-1 (WHWLQLKPGQPMY), a peptidic pheromone of Saccharomyces cerevisiae yeast, contains a XHX type copper(II) binding N-terminal site. Using a soluble analogue, WHWSKNR-amide, we demonstrated that the W(1)H(2)W(3) site alone binds copper(II) with a Kd value of 0.18 pM at pH 7.4 and also binds imidazole (Im) in a ternary complex (Kd of 1 mM at...

The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibri...

Accumulation of the β-amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimer's disease (AD). The Aβ1-x (x=16/28/40/42) peptides have been the primary focus of Cu(II) binding studies for more than 15 years; however, the N-truncated Aβ4-42 peptide is a major Aβ isoform detected in...

Accumulation of the β-amyloid (Aβ) peptide in extracellular senile plaques rich in copper and zinc is a defining pathological feature of Alzheimer′s disease (AD). The Aβ1–x (x=16/28/40/42) peptides have been the primary focus of CuII binding studies for more than 15 years; however, the N-truncated Aβ4–42 peptide is a major Aβ isoform detected in bo...

Human alpha-1 antitrypsin (AAT) is an abundant serum protein, present at a concentration of 1.0–1.5 g L−1. AAT deficiency is a genetic disease, manifesting itself with emphysema and liver cirrhosis, due to accumulation of a misfolded AAT mutant in hepatocytes. Lung AAT amount is inversely correlated with chronic obstructive pulmonary disease (COPD)...

Ni(II) ions cleave and inactivate human alpha-1 antitrypsin hydrolytically, implicating nickel exposure as a contributing factor in pathologies related to antitrypsin deficiency

Poly(ADP-ribose) polymerase 1 (PARP-1) is a key eukaryotic enzyme, catalyzing the NAD+ dependent poly(ADP-ribosyl)ation of protein substrates, crucial for major DNA repair pathways, and involved in other fundamental cellular processes, such as transcription, cell cycle control, and apoptosis. Its ability to bind DNA depends on two CCHC zinc finger...

Nickel is harmful for humans, but molecular mechanisms of its toxicity are far from being fully elucidated. One of such mechanisms may be associated with the Ni(II)-dependent peptide bond hydrolysis, which occurs before Ser/Thr in Ser/Thr-Xaa-His sequences. Human annexins A1, A2, and A8, proteins modulating the immune system, contain several such s...

The purpose of our research was to obtain peptidomimetics possessing Cu(II) and Ni(II) binding properties, which would be useful for biomedical applications. In this context we used potentiometry, UV-VIS and CD spectroscopies to characterize the Cu(II) and Ni(II) binding properties of pentapeptide analogs of the N-terminal sequence of histatin 5. T...

Hepcidin, a recently discovered vertebrate hormone, is very important for the iron metabolism. Its structure with eight cysteines forming intramolecular bonds makes it similar to defensins and metallothioneins. This is consistent with hepcidin function. It was initially discovered as a defensin like antimicrobial peptide, but in humans its primary...

In our previous research we demonstrated the sequence specific peptide bond hydrolysis of the R1-(Ser/Thr)-Xaa-His-Zaa-R2 in the presence of Ni(II) ions. The molecular mechanism of this reaction includes an N-O acyl shift of the R1 group from the Ser/Thr amine to the side chain hydroxyl group of this amino acid. The proposed role of the Ni(II) ion...

Potentiometry and UV-vis and circular dichroism spectroscopies were applied to characterize Cu(II) coordination to the Ac-GASRHWKFL-NH2 peptide. Using HPLC and ESI-MS, we demonstrated that Cu(II) ions cause selective hydrolysis of the Ala-Ser peptide bond in this peptide and characterized the pH and temperature dependence of the reaction. We found...

In previous studies we showed that Ni(II) ions can hydrolytically cleave a peptide bond preceding Ser/Thr in peptides of a general sequence RN-(Ser/Thr)-Xaa-His-Zaa-RC, where RN and RC are any peptide sequences. A peptide library screening, assisted by accurate measurements of reaction kinetics for selected peptides, demonstrated the preference for...

The binding of Ni(II) and subsequent metal-dependent hydrolysis of peptide bond occurs in sequences of peptides or proteins of the type Ser/Thr-Xaa-His. His103, His246 and His293 of human annexin A1 are located in the fragments with amino acid sequences Thr-Gly-His, Ser-Lys-His and Thr-Arg-His, respectively, which thus constitute potential nickel b...

The cooperativity of formation of 5-membered and 6-membered chelate rings is the driving force for specificity and selectivity in Cu(II) peptidic complexes. α-Amino acids enable the formation of 5-membered rings, while a 6-membered ring is provided by the coordination of the His side chain imidazole. Introduction of β-alanine is another way of crea...

Histatins are a family of human salivary antimicrobial peptides. Histatin-5 (Hst-5, DSHAKRHHGYKRKFHEKHHSHRGY), a prominent member of this family contains an albumin-like, N-terminal Asp-Ser-His sequence, known to bind a Ni(II) ion in a square-planar geometry. Nickel is a strong allergen, and oral exposure to Ni(II) ions can elicit allergic reaction...

Ni(II) ions are able to hydrolyze Naa-(Ser/Thr) peptide bonds in Naa-(Ser/Thr)-Xaa-His-Zaa sequences. We found that various human transcription factors contain such nickel hydrolytic patterns within C2H2 zinc finger (ZF) domains. We demonstrated the hydrolysis on two peptide models, the 3rd ZF of the Sp1 transcription factor and the 1st ZF of the Z...

Recently, we described a sequence-specific R1-(Ser/Thr) peptide bond hydrolysis reaction in peptides of a general sequence R1-(Ser/Thr)-Xaa-His-Zaa-R, which occurs in the presence of Ni(II) ions [A. Krężel, E. Kopera, A. M. Protas, A. Wysłouch-Cieszyńska, J. Poznański, W. Bal, J. Am. Chem. Soc. 132 (2010) 3355-3366]. In this study we explored the p...

Recently we screened a combinatorial library of R(1)-(Ser/Thr)-Xaa-His-Zaa-R(2) peptides (Xaa = 17 common alpha-amino acids, except Asp, Glu, and Cys; Zaa =19 common alpha-amino acids, except Cys; R(1) = CH(3)CO-Gly-Ala, R(2) = Lys-Phe-Leu-NH(2)) and established criteria for selecting Ser/Thr, Xaa, and Zaa substitutions optimal for specific R(1)-Se...

Parathyroid hormone (PTH) is secreted by parathyroid glands and is the main known factor that control plasma calcium concentration. There are many indications that PTH or products of PTH degradation influence the mean arterial blood pressure (MAP). These observations might be important in diseases accompanied with the overproduction of PTH such as...

SPARC (secreted protein, acidic and rich in cysteine) is a glycoprotein of the extracellular matrix that mediates the cell-matrix interactions. It plays also a role in angiogenesis, tumorigenesis, caractogenesis and wound healing. The human SPARC consists of three distinct modules. Module II is follistatin-like and its hydrolysis gives rise to a nu...