The AGDV residues on the gamma chain carboxyl terminus of platelet-bound fibrinogen are needed for platelet aggregation

Liu, Qingde; Matsueda, Gary R.; Brown, Elizabeth A.; Frojmovic, Mony M.

doi:10.1016/s0167-4838(97)00130-1

Cited by 20 publications

(19 citation statements)

References 33 publications

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“…These binding sites then interact with GPIIb/IIIa leading to platelet adhesion, activation and aggregation . Interestingly, both soluble and surface‐adsorbed Fg interact with GPIIb/IIIa primarily by the γ 400–411 sequence, with the AGDV sequence in particular mediating this function . Previous studies have also suggested that surface‐induced conformational changes to Fg result in the RGD motif of the Fg Aα chain becoming more accessible for binding to GPIIb/IIIa …”

Section: Resultsmentioning

confidence: 98%

“…Unlike the RGD motif, which is common to other proteins such as fibronectin, vitronectin and von Willlebrand's factor, the dodecapeptide sequence is unique to Fg . The dodecapeptide sequence has been shown to be the primary mediator of platelet adhesion to immobilized fibrinogen with the last four amino acid residues (AGDV) essential for this function …”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the bulk platelet response and fibrinogen interaction to elastin‐like polypeptide coatings

Srokowski

Woodhouse

2013

J Biomedical Materials Res

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In this work, we expand on our understanding of the thrombogenicity of coatings prepared with three different recombinant elastin-like polypeptides (ELPs). The bulk platelet response of the ELP coatings was characterized following whole blood contact under physiological shear flow (300 s(-1) ) using flow cytometry. Prolonged exposure to shear flow (1-h) indicated that materials coated with the longer ELP coatings (ELP2 and ELP4) had less bulk platelet activation and microparticle formation than materials coated with the shorter ELP1. Quartz crystal microbalance with dissipation (QCM-D) was used to monitor the binding of the platelet membrane receptor GPIIb/IIIa to ELP-adsorbed fibrinogen (Fg) surfaces. Compared to the shorter ELPs, a lower amount of Fg adsorbed to the ELP4 coated material and ELP4 appeared to form a softer, more structurally flexible coating layer. When Fg was adsorbed to the ELP coated surface it demonstrated an altered binding for GPIIb/IIIa that was inhibited in the presence of an AGDV-containing peptide but not an RGD-containing peptide. Conversely, on the shorter ELP coatings, binding of GPIIb/IIIa to an adsorbed Fg layer was partially inhibited in the presence of an RGD-containing peptide. These results indicate that both the quantity and conformational state of Fg varies when adsorbed to surfaces coated with ELPs of varying sequence length, which may be mediating their platelet response. Collectively, the findings reinforce the applicability of the ELPs as potential thromboresistant coatings, especially with the use of the longer polypeptide-ELP4.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Evaluation of the bulk platelet response and fibrinogen interaction to elastin‐like polypeptide coatings

Srokowski

Woodhouse

2013

J Biomedical Materials Res

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“…It plays a major role in platelet aggregation by interacting with the C-terminal part of the ␥ chain of fibrinogen. 2,3 The genes coding for GP IIb and GP IIIa are highly polymorphic. Most of the human platelet alloantigen (HPA) systems described are carried by the GP IIb-IIIa complex, and most of them are localized on the GP IIIa subunit: HPA-1, -4, -6, -7, -8, -10, -11, and one unclassified private antigen Oe a .…”

Section: Introductionmentioning

confidence: 99%

A new platelet polymorphism Duva+, localized within the RGD binding domain of glycoprotein IIIa, is associated with neonatal thrombocytopenia

Jallu¹,

Meunier²,

Brément³

et al. 2002

Blood

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IntroductionThe platelet membrane glycoprotein (GP) IIb-IIIa complex or ␣ IIb ␤ 3 belongs to the integrin family of heterodimeric adhesion receptors involved in cell-matrix and cell-cell interactions. 1 This complex can bind ligands containing the Arg-Gly-Asp (RGD) sequence, such as fibrinogen, von Willebrand factor, vitronectin, and fibronectin. It plays a major role in platelet aggregation by interacting with the C-terminal part of the ␥ chain of fibrinogen. 2,3 The genes coding for GP IIb and GP IIIa are highly polymorphic. Most of the human platelet alloantigen (HPA) systems described are carried by the GP IIb-IIIa complex, and most of them are localized on the GP IIIa subunit: , and one unclassified private antigen Oe a . [4][5][6][7][8][9][10][11] Only 2 of the platelet antigen systems, HPA-3 and -9, reside on GP IIb, 12,13 and the genetic origin of the Va a antigen remains to be determined. 14 These antigenic systems result from a single base-pair substitution with the exception of Oe a , which depends on an in-frame deletion of 3 bases. 11 Platelet alloantigen systems are involved in neonatal alloimmune thrombocytopenia (NAIT), posttransfusion purpura, and refractoriness to platelet transfusions. NAIT is characterized by the destruction of fetal or newborn platelets by a maternal antibody elicited by the maternofetal platelet antigen incompatibility. During the course of the severe thrombocytopenia in the fetus or the newborn, there is a risk of intracerebral hemorrhage leading to death or neurologic impairment. The incidence of NAIT has been shown to be 1 per 800 to 1000 live births. 15 Most NAIT in Caucasians involves HPA-1 16 or HPA-5 17 (GP Ia polymorphism 18 ) maternofetal incompatibilities.We describe here a case of severe NAIT due to a new alloantigen Duv aϩ localized on GP IIIa. The genetic determination revealed a single base-pair substitution, CϾT, at the GP IIIa complementary DNA (cDNA) position 517. This leads to a threonine/isoleucine dimorphism at position 140 of the mature GP IIIa. The Duv aϩ form of the GP IIb-IIIa complex expressed in Cos cells shows this polymorphism is responsible for the alloimmunization and the consequent NAIT. The Duv aϩ polymorphism that was localized in the RGD binding site of GP IIIa could affect the ␣ IIb ␤ 3 function. Because no individuals homozygous for Duv aϩ were available, stable cell lines expressing the Duv aϩ form of GP IIb-IIIa were produced to study a possible effect of the Duv aϩ substitution on integrin function. Materials and methods Case reportWe report a 30-year-old white woman (Duv), para 4, gravida 4, who gave birth to a full-term male child with a severe thrombocytopenia at birth (platelets 17 ϫ 10 9 /L) associated with minor bruises and petechiae. The child was otherwise healthy (Apgar score 9 of 10). He was treated with a total of 1.6 g/kg intravenous immunoglobulin G (IgG) over 24 hours. On day 3, the platelet count had increased to 139 ϫ 10 9 /L, and the outcome was favorable. Neonatal thrombocytopenia was not recorded in any of the siblin...

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“…Several adhesion proteins bind to GPIIb/IIIa, but the principle ligand is fibrinogen (5). The interaction between fibrinogen and GPIIb/IIIa involves several regions of the ligand, including the motif RGD, two copies of which are found on each ␣-chain of fibrinogen (6). Several compounds have been designed, based on the RGD sequence, as antagonists of fibrinogen binding (7,8).…”

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confidence: 99%

Glycoprotein IIb/IIIa Antagonists Induce Apoptosis in Rat Cardiomyocytes by Caspase-3 Activation

Adderley

Fitzgerald²

2000

Journal of Biological Chemistry

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The platelet integrin glycoprotein (GP) IIb/IIIa, which mediates platelet aggregation, has been the target for novel antiplatelet agents, the GPIIb/IIIa antagonists. Several GPIIb/IIIa antagonists have been developed based on the peptide RGDS present in adhesion proteins, including the principle ligand fibrinogen. The apoptosis enzyme, procaspase-3, contains an RGD-recognition sequence and is activated by RGDS. We examined the effects of RGDS and several GPIIb/IIIa antagonists on cell death and procaspase-3 activation in rat neonatal cardiomyocytes. These antagonists do not recognize rat integrins, yet RGDS, orbofiban, and xemilofiban induced dose-dependent apoptosis and procaspase-3 activation in cardiomyocytes over 72 h, particularly under hypoxic conditions. Scrambled peptide, the monoclonal antibody 7E3 or integrelin (a peptide containing a KGD sequence), had little or no effect. Immunoprecipitation of procaspase-3 followed by treatment with the compounds showed that procaspase-3 was activated directly by RGDS, orbofiban, xemilofiban, and by monoclonal 7E3 antibody, the latter demonstrating that compounds must enter cells to induce apoptosis through caspase activation. Integrelin had no effect. Binding studies with 3 H-SC52012B, a GPIIb/IIIa antagonist analogue of orbofiban, showed no specific binding to cardiomyocytes, but the radioligand accumulated intracellularly over 72 h.3 H-SC52012B also bound directly to human recombinant caspase-3 (K d , 59 ؎ 2 nm), and this was prevented by orbofiban, xemilofiban, and the monoclonal 7E3 antibody but not by integrelin. Finally confocal microscopy showed that RGDS co-localized with caspase-3 inside the cell. These data show that RGDS and its mimetics induce cardiomyocyte apoptosis by direct activation of procaspase-3.

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The AGDV residues on the gamma chain carboxyl terminus of platelet-bound fibrinogen are needed for platelet aggregation

Cited by 20 publications

References 33 publications

Evaluation of the bulk platelet response and fibrinogen interaction to elastin‐like polypeptide coatings

Evaluation of the bulk platelet response and fibrinogen interaction to elastin‐like polypeptide coatings

A new platelet polymorphism Duva+, localized within the RGD binding domain of glycoprotein IIIa, is associated with neonatal thrombocytopenia

Glycoprotein IIb/IIIa Antagonists Induce Apoptosis in Rat Cardiomyocytes by Caspase-3 Activation

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