Evidence that the primary binding site of von Willebrand factor that mediates platelet adhesion on subendothelium is not collagen.

Groot, Philip G. de; Ottenhof-Rovers, Mieke; Mourik, Jan A. van; Sixma, JJ

doi:10.1172/jci113602

Cited by 74 publications

(37 citation statements)

References 35 publications

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“…Radioactive [19]; CLB-RAg 201 inhibits binding of vWF to collagen type I and 111, and recognizes an epitope located between residues 911 and 1365 [19]. CLB-RAg 38 inhibits binding of vWF to the vessel wall and recognizes an epitope on a carboxy-terminal80-kDa fragment of vWF [20]. vWF-9 is a monoclonal antibody directed against vWF, inhibiting the binding of vWF to platelets activated by thrombin.…”

Section: Methodsmentioning

confidence: 99%

Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin

Sixma¹,

Schiphorst²,

Verweij

et al. 1991

European Journal of Biochemistry

107

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In order to study the functional importance of the collagen, heparin and glycoprotein-Ib-binding domain, we deleted the A1 domain of von Willebrand factor (vWF), corresponding to residues 478 -716, by oligonucleotidedirected mutagenesis. The resulting AAI-vWF cDNA was expressed in COS-1 monkey kidney cells and compared to wild-type vWF. The higher-molecular-mass multimers were decreased in A A1 recombinant von Willebrand factor (AAl-rvWF) compared to plasma vWF and rvWF. The reactivity of AAl-rvWF and rvWF with monoclonal antibodies directed against the collagen-binding domain (residues 969 -992), the vessel-wall-binding domain, and the binding site for glycoprotein IIb-IIIa on platelets was identical. The interaction with vWF of the monoclonal antibody directed against the glycoprotein Ib binding domain was abolished for AAl-rvWF, and similar to plasma vWF for rvWF. The binding of factor VIII to AAl-rvWF and rvWF was similar. dAl-rvWF and rvWF bound similarly to collagen, but the binding of AAl-rvWF to heparin and to platelets in the presence of ristocetin were abolished. These data indicate that the heparin-binding site in the A1 domain is essential. There is no second binding domain for glycoprotein Ib outside the A1 domain. The collagen-binding domain in the A1 domain is either not active or its action can be compensated by the second collagen-binding domain.Von Willebrand factor (vWF) is a multimeric glycoprotein with a basic subunit of 270 kDa, which dimerizes at its carboxy-terminus through disulphide bonding. Multimers are formed by further disulphide bonding at the amino-terminus of the molecule [l, 21. vWF is encoded by mRNA (as deduced from the cDNA) with an open reading frame of 8439 nucleotides, corresponding to a primary translation product of approximately 370 kDa. This prepro-vWF contains a signal peptide of 22 amino acids and a propolypeptide of 741 amino acids [3-61. The propolypeptide has also been termed von Willebrand antigen 11. It has been shown to be involved in multimer formation [7, 81. vWF is composed of a number of repeats with a considerable degree of sequence similarity. These various repeats are illustrated in Fig. 1 still, two discontinuous short domains of 15 amino acids each (474-488 and 695 -708), linked by a disulphide bond, were found to contain the GPIb domain [14]. GPIIb-IIIa is probably represented by the RGD sequence at residues 1744-1747. The RGD sequence has also been encountered in fibrinogen, fibronectin and vitronectin, and binding of all of these proteins to GPIIb-IIIa is inhibited by RGD-containing peptides [15, 161. In this study, we have tried to investigate the importance of the GPIb, heparin and collagen domains located at residues 449 -728 for vWF function. We have made use of the observation that this region of the molecule corresponds well with one of the repeating homologous areas. The A1 domain (residues 478 -716) was deleted and the mutant vWF cDNA was expressed in monkey kidney COS-1 cells. Such an approach seems justified, because recent studies on m...

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Section: Methodsmentioning

confidence: 99%

Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin

Sixma¹,

Schiphorst²,

Verweij

et al. 1991

European Journal of Biochemistry

107

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“…However, the significance of fibrillar collagen interactions is challenged by reports that VWF binds normally to extracellular matrix that is depleted of collagen either by collagenase digestion or by growth of cells in the presence of α,α -dipyridyl, a collagen synthesis inhibitor (59). Also, monoclonal antibodies to VWF have been characterized that prevent VWF binding to either extracellular matrix or fibrillar collagens, but not both (60). These findings have focused attention on other candidates.…”

Section: Platelet Adhesion To Connective Tissuementioning

confidence: 99%

Biochemistry and Genetics of Von Willebrand Factor

Sadler

1998

Annu. Rev. Biochem.

1,249

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Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical ≈250 kDa subunits into disulfide-linked multimers that may be >20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clincial symptoms and the response to therapy. CONTENTS

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“…Once VWF is immobilized in the extracellular matrix, however, platelets bind and adhere tightly to it. This apparent induction of GPIb␣ binding in vivo is associated with VWF binding to collagen (9,10) or other subendothelial components (11,12). High affinity binding of VWF to GPIb␣ is induced in vitro by certain exogenous modulators, including the antibiotic ristocetin (13,14) and the snake venom protein botrocetin (15).…”

Section: Von Willebrand Factor (Vwf)mentioning

confidence: 99%

Interaction of von Willebrand Factor Domain A1 with Platelet Glycoprotein Ibα-(1–289)

Miura¹,

Li²,

Cao³

et al. 2000

Journal of Biological Chemistry

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. VWF A1 and A1(R545A) bound to platelets with affinities and rate constants similar to those for binding to GPIb␣-CaM, and botrocetin had the expected positively cooperative effect on the binding of VWF A1 to GPIb␣-CaM. Therefore, allosteric regulation by botrocetin of VWF A1 binding to GPIb␣, and the increased binding affinity caused by mutations in VWF or GPIb␣, are reproduced by isolated structural domains. The substantial increase in k on caused by mutations in either A1 or GPIb␣ suggests that productive interaction requires rate-limiting conformational changes in both binding sites. The exceptionally slow k on and k off provide important new constraints on models for rapid platelet tethering at high wall shear rates.

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Evidence that the primary binding site of von Willebrand factor that mediates platelet adhesion on subendothelium is not collagen.

Cited by 74 publications

References 35 publications

Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin

Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin

Biochemistry and Genetics of Von Willebrand Factor

Interaction of von Willebrand Factor Domain A1 with Platelet Glycoprotein Ibα-(1–289)

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