Zinc potentiates the antibacterial effects of histidine‐rich peptides against <i>Enterococcus faecalis</i>

Rydengård, Victoria; Nordahl, Emma Andersson; Schmidtchen, Artur

doi:10.1111/j.1742-4658.2006.05246.x

Cited by 49 publications

(59 citation statements)

References 35 publications

(38 reference statements)

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“…Binding of heparin to His residues is also consistent with the Zn 2ϩ dependence of the interaction. His residues represent the principal coordination site for metal ions in numerous metal-binding proteins (34,35). Confirming (4,5).…”

Section: Discussionmentioning

confidence: 99%

Zn2+ Mediates High Affinity Binding of Heparin to the αC Domain of Fibrinogen

Fredenburgh

Leslie

Stafford

et al. 2013

Journal of Biological Chemistry

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Background:The interaction of heparin with fibrinogen compromises its anticoagulant activity. Results: Zn 2ϩ promotes heparin binding to His-544 -His-545 on the fibrinogen ␣-chain. Conclusion: We identified a novel Zn 2ϩ -dependent heparin binding site on fibrinogen. Significance: Platelet release of Zn 2ϩ at sites of vascular injury may promote heparin binding to fibrinogen, thereby further attenuating the anticoagulant activity of heparin.

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Section: Discussionmentioning

confidence: 99%

Zn2+ Mediates High Affinity Binding of Heparin to the αC Domain of Fibrinogen

Fredenburgh

Leslie

Stafford

et al. 2013

Journal of Biological Chemistry

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“…The capacity of HRG to enhance bacterial killing has been localized to its NH 2 -terminal and HRR domains. Thus, in the presence of Zn 2ϩ or when the pH is low, HRG induces lysis of the bacterial cell wall (19,20). These conditions can occur at sites of injury or wound-healing where activated platelets release Zn 2ϩ and local ischemia lowers pH (13,52).…”

Section: Discussionmentioning

confidence: 99%

“…Zn 2ϩ is important for the binding of HRG to bacteria, cells, and hemostatic factors, such as glycosaminoglycans, plasminogen, and factor XIIa (12,19,24,34). It is likely that there are still other HRG interactions that have been overlooked because of the widespread use of citrate as an anticoagulant.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its potential role in hemostasis, HRG also has been implicated in innate immunity and inflammation (18). HRG exhibits antifungal and antimicrobial activity in vitro, and these activities are enhanced at low pH or in the presence of Zn 2ϩ , conditions that promote ligand binding (19,20). The antimicrobial activity of HRG has also been demonstrated in vivo and appears to be fibrin-dependent.…”

mentioning

confidence: 91%

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Histidine-rich Glycoprotein Binds Fibrin(ogen) with High Affinity and Competes with Thrombin for Binding to the γ′-Chain

Stafford

Leslie

et al. 2011

Journal of Biological Chemistry

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Histidine-rich glycoprotein (HRG) is an abundant protein that binds fibrinogen and other plasma proteins in a Zn2؉ -dependent fashion but whose function is unclear. HRG has antimicrobial activity, and its incorporation into fibrin clots facilitates bacterial entrapment and killing and promotes inflammation. Although these findings suggest that HRG contributes to innate immunity and inflammation, little is known about the HRGfibrin(ogen) interaction. By immunoassay, HRG-fibrinogen complexes were detected in Zn 2؉ -supplemented human plasma, a finding consistent with a high affinity interaction. Fibrinogen is the soluble precursor of fibrin, a critical component of blood clots that endows them with strength and elasticity. Fibrinogen is a glycoprotein composed of three pairs of polypeptide chains, termed A␣, B␤, and ␥, that are connected by disulfide bonds (1). Approximately 10 -15% of circulating fibrinogen has a variant ␥-chain termed the ␥Ј-chain, which results from differential processing of the ␥ A -chain mRNA transcript (2-4). The ␥Ј-chain is distinguished from the ␥ A -chain by the presence of an acidic 20-residue extension at its COOH terminus (2, 5).Thrombin catalyzes the conversion of fibrinogen to insoluble fibrin, and during this process some thrombin remains bound to the fibrin network (6). Exosites 1 and 2 are two regulatory domains that flank the active site of thrombin and mediate its binding to fibrin (7,8). Exosite 1 of thrombin interacts with the central E-domain of fibrin, whereas exosite 2 binds only to the COOH terminus of the ␥Ј-chain. Consequently, thrombin binds ␥ A /␥ A -fibrin in a univalent fashion with a K d value of 2-4 M. In contrast, both exosites are engaged when thrombin binds to ␥ A /␥Ј-fibrin, resulting in a higher affinity interaction (K d value of 0.08 -0.18 M) (5, 9). Fibrin-bound thrombin remains active, and the protease is protected from inhibition by fluid-phase inhibitors, such as antithrombin and heparin cofactor II (6). Because of its bivalent interaction with ␥ A /␥Ј-fibrin, thrombin bound to ␥ A /␥Ј-fibrin is more protected from inhibition by fluid-phase inhibitors than thrombin bound to ␥ A /␥ Afibrin (10).Like thrombin, histidine-rich glycoprotein (HRG) 3 binds to fibrinogen and is incorporated into fibrin clots (11). Although the plasma concentration of HRG ranges from 1.6 to 2 M, the concentration in platelet-rich thrombi may be higher because HRG is stored in the alpha granules of platelets and is released when platelets are activated (12, 13). A 75-kDa glycoprotein, HRG, is composed of two NH 2 -terminal cystatin-like domains, a central histidine-rich region (HRR) flanked by two prolinerich regions, and a COOH-terminal domain (14). In addition to fibrinogen, HRG also binds plasminogen, heparan sulfate, and divalent cations, such as Zn 2ϩ (12,15,16). Therefore, HRG is hypothesized to be an important accessory or adapter protein that brings different ligands together under specific conditions (14).HRG-deficient mice exhibit a shorter prothrombin time and accelerat...

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“…Zinc binding was shown to allow Hst 5 to catalyze fusion of lipid vesicles (73), and some increase in the bactericidal activity for Hst 5 has been reported for Zn-Hst 5 (75). However, effects of Cu binding provide unique mechanistic insights into novel potential candidacidal mechanisms for Hst 5.…”

Section: Hst 5 Metal Binding Abilities As a Potential Candidacidal Mementioning

confidence: 99%

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

2014

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Histatins are salivary cationic peptides that provide the first line of defense against oral candidiasis caused by Candida albicans. This minireview presents a critical evaluation of our knowledge of the candidacidal mechanism of histatin 5 (Hst 5). Hst 5 is the most potent among all histatin family members with regard to its antifungal activity. The mode of action of Hst 5 has been a subject of intense debate. Unlike other classical host innate immune proteins, pore formation or membrane lysis by Hst 5 has largely been disproven, and it is now known that all targets of Hst 5 are intracellular. Hst 5 binds C. albicans cell wall proteins (Ssa1/2) and glycans and is taken up by the cells through fungal polyamine transporters in an energy-dependent manner. Once inside the fungal cells, Hst 5 may affect mitochondrial functions and cause oxidative stress; however, the ultimate cause of cell death is by volume dysregulation and ion imbalance triggered by osmotic stress. Besides these diverse targets, a novel mechanism based on the metal binding abilities of Hst 5 is discussed. Finally, translational approaches for Hst 5, based on peptide design and synergy with other known drugs, are considered a step forward for bench-to-bed application of Hst 5.

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Zinc potentiates the antibacterial effects of histidine‐rich peptides against Enterococcus faecalis

Abstract: AbbreviationsHMWK, high molecular weight kininogen; SDS-PAGE, SDS-polyacrylamide gel electrophoresis. Keywords

Cited by 49 publications

References 35 publications

Zn2+ Mediates High Affinity Binding of Heparin to the αC Domain of Fibrinogen

Zn2+ Mediates High Affinity Binding of Heparin to the αC Domain of Fibrinogen

Histidine-rich Glycoprotein Binds Fibrin(ogen) with High Affinity and Competes with Thrombin for Binding to the γ′-Chain

How Does It Kill?: Understanding the Candidacidal Mechanism of Salivary Histatin 5

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