Inhibition of fibrinogen binding to human platelets by the tetrapeptide glycyl-L-prolyl-L-arginyl-L-proline.

Plow, Edward F.; Marguerie, G

doi:10.1073/pnas.79.12.3711

Cited by 72 publications

(37 citation statements)

References 30 publications

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“…Washed platelets were obtained by differential centrifugation followed by gel filtration. Fixed platelets were prepared (24) by stimulating washed platelets with a solution of 10 M ADP plus 20 M epinephrine and then fixing them with 1% paraformaldehyde. This protocol fixes integrin ␣ IIb ␤ 3 in an activated state, thereby limiting the effects of TSP-1 added to the aggregation rather than the activation step of the plateletplatelet interaction (25,26).…”

Section: Methodsmentioning

confidence: 99%

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Narizhneva

Byers-Ward

Quinn

et al. 2004

Journal of Biological Chemistry

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A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated with early onset myocardial infarction.

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Section: Methodsmentioning

confidence: 99%

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Narizhneva

Byers-Ward

Quinn

et al. 2004

Journal of Biological Chemistry

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“…Conversely, RGD-containing peptides can act as competitive inhibitors of ligand binding. [4][5][6][7] For example, the RGD motif located in the C1 domain of VWF [8][9][10] appears to be necessary for VWF binding to ␣IIb␤3, and the RGD-mimetic small molecules tirofiban and eptifibatide are competitive inhibitors of fibrinogen binding to ␣IIb␤3. 11,12 Nonetheless, the interaction of ligands with integrins, such as ␣IIb␤3, is substantially more complex than would be predicted from these experiments.…”

Section: Introductionmentioning

confidence: 99%

“…The prototypic example of integrin regulation is the platelet integrin ␣IIb␤3; on resting platelets, ␣IIb␤3 is inactive, but after platelet stimulation, it assumes an active conformation that enables it to bind macromolecular ligands, such as fibrinogen and von Willebrand factor (VWF). 3 Many integrin ligands contain an arginine-glycineaspartic acid (RGD) motif [4][5][6] that participates in integrin binding. Conversely, RGD-containing peptides can act as competitive inhibitors of ligand binding.…”

Section: Introductionmentioning

confidence: 99%

Species differences in small molecule binding to αIIbβ3 are the result of sequence differences in 2 loops of the αIIb β propeller

Basani

Zhu

Thornton

et al. 2009

Blood

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Compared with human platelets, rodent platelets are less responsive to peptides and peptidomimetics containing an arginineglycine-aspartic acid (RGD) motif. Using chimeric human-rat ␣IIb␤3 molecules, we found that this difference in Arg-Gly-Asp-Ser (RGDS) sensitivity was the result of amino acid substitutions at residues 157, 159, and 162 in the W3:4-1 loop and an Asp-His replacement at residue 232 in the W4:4-1 loop of the ␣IIb ␤ propeller. Introducing the entire rat W3:4-1 and W4:4-1 loops into human ␣IIb␤3 also decreased the inhibitory effect of the disintegrins, echistatin and eristostatin, and the ␣IIb␤3 antagonists, tirofiban and eptifibatide, on fibrinogen binding, whereas the specific point mutations did not. This suggests that RGDS interacts with ␣IIb in a different manner than with these small molecules. None of these speciesbased substitutions affected the ability of ␣IIb␤3 to interact with RGD-containing macromolecules. Thus, human von Willebrand factor contains an RGD motif and binds equally well to adenosine diphosphatestimulated human and rodent platelets, implying that other motifs are responsible for maintaining ligand binding affinity. Many venoms contain RGD-based toxins. Our data suggest that these species amino acids differences in the ␣IIb ␤-propeller represent an evolutionary response by rodents to maintain hemostasis while concurrently protecting against RGD-containing toxins.

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“…10 Peptide GPRP, which is analogous to the Nterminal of both the ␣ and ␤ chains of fibrinogen, is able to inhibit fibrin polymerization, but it also inhibits platelet aggregation at high concentration in vitro and in vivo. 21,22 In order to better dissect the importance of fibrinogen-platelet integrin interactions and fibrin polymer formation in thrombus formation and stability, we monitored thrombus growth in Fg␥⌬5 mice by using the intravital microscopy thrombosis model. 10,23,24 We report here that, despite the preservation of fibrin polymer formation in Fg␥⌬5, these mice exhibit a distinct and significant defect in thrombus stability.…”

Section: Introductionmentioning

confidence: 99%

Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen γ chain

Papalia

Degen

et al. 2003

Blood

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Fibrin(ogen) deficiency (Fg -/-) was shown previously to be compatible with rapid thrombus growth within injured arterioles, but platelet fibronectin content was increased and newly formed thrombi were unstable. To further define the role of fibrin(ogen) in thrombus formation and stabilization, platelet biology was examined in mice expressing a form of fibrinogen that clots normally but lacks the ␥ chain C-terminal binding site for ␣IIb␤3 (Fg␥⌬5). Thrombus growth within the arterioles of Fg␥⌬5 mice appeared faster than in wild-type mice despite a far greater emboli formation. Unlike Fg -/-mice, the emboli were relatively small and released from the top of thrombi, rather than by fracture at the vessel wall. The fibronectin content in Fg␥⌬5 platelets was also dramatically increased through a ␤3 integrindependent mechanism. The following has been concluded: (1) Fibrin formation contributes to, but is not sufficient for, the stabilization of arterial thrombi. Platelet receptor engagement of the C-terminal of the Fg ␥ chain contributes to the stable incorporation of platelets into thrombi. IntroductionArrest of bleeding at the site of injury is mediated by the adhesion and aggregation of platelets and the formation of the polymerized fibrin matrix. The same general process contributes to the generation of inopportune thrombi within atherosclerotic arteries. Thrombosis in coronary or cerebral arteries is a major cause of morbidity and mortality worldwide. It has been demonstrated that platelet membrane glycoprotein (GP) Ib complex and its ligand, von Willebrand factor (VWF), are involved in initiating platelet adhesion, particularly at high shear. 1 Subsequent stable platelet adhesion and aggregation are mediated by several integrin receptors and their ligands, such as ␣2␤1/collagen and ␣IIb␤3/fibrinogen (Fg) or VWF. 1,2 The GPIb complex is also involved in platelet aggregation. [3][4][5] In contrast to static or low shear conditions, where fibrinogen is necessary for platelet aggregation, 6,7 at high shear efficient platelet aggregation can occur independently of Fg 8-10 and even independently of both VWF and Fg. 10 Under these conditions, fibronectin (Fn) 11 and perhaps other molecules are able to support platelet aggregation. However, fibrinogen and the local conversion of fibrinogen to fibrin by thrombin are generally thought to be indispensable in stabilizing the thrombus. 9,10 Fibrinogen is a 340-kDa glycoprotein dimer consisting of 2 sets of 3 polypeptide chains, termed the A␣, B␤, and ␥ chains. Fibrinogen both provides the fundamental building block for assembly of provisional fibrin matrices and supports cell adhesion through specific integrin and nonintegrin receptor binding motifs. The C-terminal of the ␥ chain contains a critical binding site for the platelet integrin receptor, ␣IIb␤3 (GPIIbIIIa), which has been demonstrated to be required for platelet aggregation. 12,13 Fg from Fg␥⌬5 mice, carrying the genetically modified form of the ␥ chain gene, which eliminates the last 5 residues (QAGDV) of the ␥ ...

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Inhibition of fibrinogen binding to human platelets by the tetrapeptide glycyl-L-prolyl-L-arginyl-L-proline.

Cited by 72 publications

References 30 publications

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Molecular and Functional Differences Induced in Thrombospondin-1 by the Single Nucleotide Polymorphism Associated with the Risk of Premature, Familial Myocardial Infarction

Species differences in small molecule binding to αIIbβ3 are the result of sequence differences in 2 loops of the αIIb β propeller

Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen γ chain

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