Effects of Metal Ions on Activity of Plasmin

Nowak, Paweł; Zgirski, Alojzy

doi:10.1385/bter:93:1-3:87

Cited by 8 publications

(4 citation statements)

References 12 publications

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“…It should be noted that plasmin-mediated cleavage of HRG is negatively regulated when Zn 2+ is present or when physiological pH is acidic [28,80]. The exact mechanism behind acidic pH or presence of Zn 2+ regulating HRG proteolysis remains unclear.…”

Section: Plasmin-mediated Cleavage Of Hrg Alters Its Biological Fumentioning

confidence: 99%

Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury

et al. 2017

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Divalent metal ions are essential nutrients for all living organisms and are commonly protein-bound where they perform important roles in protein structure and function. This regulatory control from metals is observed in the relatively abundant plasma protein histidine-rich glycoprotein (HRG), which displays preferential binding to the second most abundant transition element in human systems, Zinc (Zn2+). HRG has been proposed to interact with a large number of protein ligands and has been implicated in the regulation of various physiological and pathological processes including the formation of immune complexes, apoptotic/necrotic and pathogen clearance, cell adhesion, antimicrobial activity, angiogenesis, coagulation and fibrinolysis. Interestingly, these processes are often associated with sites of tissue injury or tumour growth, where the concentration and distribution of Zn2+ is known to vary. Changes in Zn2+ levels have been shown to modify HRG function by altering its affinity for certain ligands and/or providing protection against proteolytic disassembly by serine proteases. This review focuses on the molecular interplay between HRG and Zn2+, and how Zn2+ binding modifies HRG-ligand interactions to regulate function in different settings of tissue injury.

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Section: Plasmin-mediated Cleavage Of Hrg Alters Its Biological Fumentioning

confidence: 99%

Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury

et al. 2017

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“…Why the streptokinases and staphylokinases shared a common property that addition of Zn 2+ and Cu 2+ resulted in almost completely inhibition of activities? Because the plasmin completely lost its activity when it was incubated with Zn 2+ and Cu 2+ [32, 33]. …”

Section: Resultsmentioning

confidence: 99%

Highly Effective Renaturation of a Streptokinase fromStreptococcus pyogenesDT7 as Inclusion Bodies Overexpressed inEscherichia coli

Nguyen

Quyen

2014

BioMed Research International

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The streptokinase (SK) is emerging as an important thrombolytic therapy agent in the treatment of patients suffering from cardiovascular diseases. We reported highly effective renaturation of a SK from S. pyogeness DT7 overexpressed in E. coli, purification, and biochemical characterization. A gene coding for the SK was cloned from S. pyogeness DT7. Because accumulation of active SK is toxic to the host cells, we have expressed it in the form of inclusion bodies. The mature protein was overexpressed in E. coli BL21 DE3/pESK under the control of the strong promoter tac induced by IPTG with a level of 60% of the total cell proteins. The activity of the rSK, renatured in phosphate buffer supplemented with Triton X-100 and glycerol, was covered with up to 41 folds of its initial activity. The purified of protein was identified with MALDI-TOF mass spectrometry through four peptide fragments, which showed 100% identification to the corresponding peptides of the putative SK from GenBank. Due to overexpression and highly effective renaturation of large amounts of inclusion bodies, the recombinant E. coli BL21 DE3/pESK system could be potentially applied for large-scale production of SK used in the therapy of acute myocardial infarction.

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“…Similarly, acidic pH and the presence of Zn 2+ directly inhibited plasmin activity ( Figure 6C), as well as substantially reducing the cleavage of HRG by plasmin ( Figure 6D). Indeed, the ability of Zn 2+ to inhibit plasmin activity has been shown previously to abolish the proteolytic cleavage of fibrinogen by plasmin [39]. In addition, under conditions of tissue injury when the local concentration of Zn 2+ is elevated [31] and the pH is acidic [29,30], HRG can bind more effectively to cell surface HS [14,21], thereby masking plasmin cleavage sites and possibly further delaying the proteolytic cleavage of HRG by plasmin.…”

Section: Discussionmentioning

confidence: 99%

Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage

Poon

Olsson

Hulett

et al. 2009

Biochemical Journal

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The plasminogen/plasmin system is involved in a variety of normal physiological and pathological processes, including tissue remodelling, angiogenesis and tumour metastasis. Plasminogen activators and receptors for plasminogen/plasminogen activators are essential for the processing of plasminogen to form the active serine protease plasmin. Plasmin can in turn positively or negatively regulate further plasminogen activation via plasmin-mediated cleavage of receptors and activators. HRG (histidine-rich glycoprotein), a relatively abundant (approx. 100-150 microg/ml) plasma glycoprotein, has a multi-domain structure that can interact with many ligands, including Zn2+, heparin, HS (heparan sulfate) and plasminogen. HRG has been shown to function as an adaptor molecule to tether plasminogen to GAG (glycosaminoglycan)-bearing surfaces and to regulate plasminogen activation via various mechanisms. As HRG itself is sensitive to plasmin cleavage, the present study examines in detail the cleavage of human HRG by plasmin and the effect of this cleavage on various functions of HRG. HRG fragments, generated by plasmin cleavage, are held together by disulfide linkages and are not released from the molecule under non-reducing conditions. Plasmin-mediated cleavage partially inhibited HRG binding to cell surface HS, but enhanced HRG binding to necrotic cells and to plasminogen. However, both intact and plasmin-cleaved HRG enhanced the binding of plasminogen to heparin-coated surfaces to a similar extent. Furthermore, the presence of heparin, Zn2+ or acidic pH was found to protect HRG from plasmin cleavage. Thus proteolytic cleavage of HRG by plasmin may provide a feedback mechanism to regulate the effects of HRG on the plasminogen/plasmin system and other functions of HRG.

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Effects of Metal Ions on Activity of Plasmin

Cited by 8 publications

References 12 publications

Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury

Functional Regulation of the Plasma Protein Histidine-Rich Glycoprotein by Zn2+ in Settings of Tissue Injury

Highly Effective Renaturation of a Streptokinase fromStreptococcus pyogenesDT7 as Inclusion Bodies Overexpressed inEscherichia coli

Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage

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