Histidine-rich glycoprotein plus zinc to neutralize heparin

Fu, Chieh-Lin; Horn, McDonald K.

doi:10.1067/mlc.2002.121854

Cited by 13 publications

(12 citation statements)

References 28 publications

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“…Under similar conditions, HRG will elute from immobilized heparin in the presence of 1M NaCl. 34 This is significant in that, because HRG is reported to bind more tightly to heparin than any other plasma protein, 41,42 conceivably HRPII could out-compete all other proteins for binding to GAGs, such as heparan sulfate and dermatan sulfate on the endothelial surface during P falciparum infection. HRPII has been shown to coat the vascular endothelium in humans with falciparum malaria.…”

Section: Discussionmentioning

confidence: 99%

“…Presumably, HRPII would also affect the AT inhibition of its other coagulation targets. Although other plasma proteins that bind GAGs, including HRG, platelet factor 4, and serum amyloid P, have been reported to neutralize heparin, 41,48,49 only HRG has been reported to do so in the plasma environment. 26 Consequently, if HRPII affects heparin activity in plasma, it might interfere with the physiologic functions of HRG in blood.…”

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confidence: 99%

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Inhibition of antithrombin by Plasmodium falciparum histidine-rich protein II

Ndonwi¹,

Burlingame²,

Miller³

et al. 2011

Blood

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Histidine-rich protein II (HRPII) is an abundant protein released into the bloodstream by Plasmodium falciparum, the parasite that causes the most severe form of human malaria. Here, we report that HRPII binds tightly and selectively to coagulation-active glycosaminoglycans (dermatan sulfate, heparan sulfate, and heparin) and inhibits antithrombin (AT). In purified systems, recombinant HRPII neutralized the heparin-catalyzed inhibition of factor Xa and thrombin by AT in a Zn 2؉ -dependent manner. The observed 50% inhibitory concentration (IC 50 ) for the HRPII neutralization of AT activity is approximately 30nM for factor Xa inhibition and 90nM for thrombin inhibition. Zn 2؉ was required for these reactions with a distribution coefficient (K d ) of approximately 7M. Substituting Zn 2؉ with Cu 2؉ , but not with Ca 2؉ , Mg 2؉ , or Fe 2؉ , maintained the HRPII effect. HRPII attenuated the prolongation in plasma clotting time induced by heparin, suggesting that HRPII inhibits AT activity by preventing its stimulation by heparin. In the microvasculature, where erythrocytes infected with P falciparum are sequestered, high levels of released HRPII may bind cellular glycosaminoglycans, prevent their interaction with AT, and thereby contribute to the procoagulant state associated with P falciparum infection. (Blood. 2011;117(23): 6347-6354) IntroductionMalaria is an ancient parasitic disease that continues to take an enormous toll on persons and communities, as well as on global economies. In humans, the disease is caused by 5 protozoan parasites of the genus Plasmodium, including P ovale, P malariae, P vivax, P knowlesi, and P falciparum. Current infection rates are estimated at 250 million annually, with approximately 1 million of those cases resulting in fatalities. 1,2 P falciparum infection is the most dreaded, accounting for almost all malaria deaths. Morbidity and mortality from P falciparum malaria result from serious complications that arise during the course of the infection, including severe anemia, neurologic impairment, acute renal failure, and coagulopathy. Coagulation disturbances may contribute to the inflammation and organ failure associated with severe disease. 3,4 Patients with P falciparum infections have prolonged prothrombin time and activated partial thromboplastin time (aPTT), 5,6 reduced levels of clotting factors, including antithrombin (AT), 7,8 and elevated levels of fibrin degradation products. 9,10 Although uncommon, frank disseminated intravascular coagulation is observed in severe cases. 5,9,11 Activation of the intrinsic coagulation cascade and induction of tissue factor expression have been proposed, [12][13][14] but the precise mechanisms leading to hemostatic alterations in P falciparum infection remain poorly understood. Whether secreted parasite products are involved has not been established. Products released by intraerythrocytic parasites include a pair of proteins with unusually high histidine content: histidine-rich protein II (HRPII) and HRPIII. 15 Of these 2 homologous proteins...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of antithrombin by Plasmodium falciparum histidine-rich protein II

Ndonwi¹,

Burlingame²,

Miller³

et al. 2011

Blood

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“…It is well known that HPRG binding to soluble heparin and to heparan sulfate is mediated by histidine residues and it is highly dependent on the presence of Zn 2þ and on pH variations [43,44]. Furthermore, the binding of the HPRR domain to heparinSepharose occurs at a slightly acidic pH (pH 6.8) and the heparin binding is abolished by the modification of histidine residues [45].…”

Section: The Histidine-proline-rich Central Region Of Hprg: Potentialmentioning

confidence: 99%

“…However, the role of HPRG as a plasma Zn binding protein is questionable since the major part of exchangeable zinc binds to albumin or a2-macroglobulin. It has been calculated that, in the presence of other serum proteins that compete for zinc, the metal is bound to only 1% of the putative HPRG zinc binding sites [43].…”

Section: The Histidine-proline-rich Central Region Of Hprg: Potentialmentioning

confidence: 99%

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Ronca

Raggi

2015

Biochimie

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“…64,[66][67][68] Furthermore, the presence of Zn 2ϩ that is released by activated platelets, 69 can potentiate the interaction between HRG and heparin, 21,64 and the ability of HRG to neutralize heparin. 70,71 Interestingly, HRG can also interact with fibrinogen and be incorporated into fibrin clots. 15 Although it was observed that HRG had no effect on the extent of fibrinogen conversion into fibrin by thrombin during the formation of fibrin clots, the presence of HRG did retard the rate of conversion of fibrinogen to fibrin.…”

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confidence: 99%

Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma

Poon

Patel

Davis

et al. 2011

Blood

199

209

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Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glyco-protein, is an abundant and well-characterized protein of vertebrate plasma. HRG has a multidomain structure that allows the molecule to interact with many ligands, including heparin, phospholipids, plasminogen, fibrinogen, immunoglobulin G, C1q, heme, and Zn²(+). The ability of HRG to interact with various ligands simultaneously has suggested that HRG can function as an adaptor molecule and regulate numerous important biologic processes, such as immune complex/necrotic cell/pathogen clearance, cell adhesion, angiogenesis, coagulation, and fibrinolysis. The present review covers the proposed multifunctional roles of HRG with a focus on recent findings that have led to its emergence as a key regulator of immunity and vascular biology. Also included is a discussion of the striking functional similarities between HRG and other important multifunctional proteins found in plasma, such as C-reactive protein, C1q, β₂ glycoprotein I, and thrombospondin-1.

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Histidine-rich glycoprotein plus zinc to neutralize heparin

Cited by 13 publications

References 28 publications

Inhibition of antithrombin by Plasmodium falciparum histidine-rich protein II

Inhibition of antithrombin by Plasmodium falciparum histidine-rich protein II

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma

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