Structural basis of von Willebrand factor binding to platelet glycoprotein Ib and collagen. Effects of disulfide reduction and limited proteolysis of polymeric von Willebrand factor.

Bockenstedt, Paula; Greenberg, Josh; Handin, Robert I.

doi:10.1172/jci112369

Cited by 46 publications

(20 citation statements)

References 47 publications

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“…Similar conclusions were drawn by Feys et al using immunoprecipitation of VWF-ADAMTS13 complexes in solution to determine a K D ϳ 79nM. 63 This interaction was dependent on the ADAMTS13 TSP [2][3][4][5][6][7][8] repeats. Both studies demonstrated the specific binding of ADAMTS13 to globular VWF, and that in the absence of shear-induced unfolding of VWF this interaction is nonproductive in terms of VWF proteolysis.…”

Section: Adamts13 Recognition Of Globular Vwfsupporting

confidence: 67%

“…1 It is a multiadhesive protein that can interact with cell surface, extracellular matrix, and plasma protein ligands through specific domain binding sites. [2][3][4][5][6] VWF is synthesized as a multimeric protein, which is central to its physiologic role. VWF function as a vessel wall damage sensor and initiator of primary hemostasis is highly dependent on its multimeric size.…”

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confidence: 99%

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Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor

Crawley

Groot

Xiang

et al. 2011

Blood

256

246

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von Willebrand factor (VWF) is a large adhesive glycoprotein with established functions in hemostasis. It serves as a carrier for factor VIII and acts as a vascular damage sensor by attracting platelets to sites of vessel injury. VWF size is important for this latter function, with larger multimers being more hemostatically active. Functional imbalance in multimer size can variously cause microvascular thrombosis or bleeding. The regulation of VWF multimeric size and platelet-tethering function is carried out by ADAMTS13, a plasma metalloprotease that is constitutively active. Unusually, protease activity of ADAMTS13 is controlled not by natural inhibitors but by conformational changes in its substrate, which are induced when VWF is subject to elevated rheologic shear forces. This transforms VWF from a globular to an elongated protein. This conformational transformation unfolds the VWF A2 domain and reveals cryptic exosites as well as the scissile bond. To enable VWF proteolysis, ADAMTS13 makes multiple interactions that bring the protease to the substrate and position it to engage with the cleavage site as this becomes exposed by shear. This article reviews recent literature on the interaction between these 2 multidomain proteins and provides a summary model to explain proteolytic regulation of VWF by ADAMTS13. Many of the coordinated processes involved in hemostasis are driven by proteolytic reactions in which proteases cleave specific substrate bonds. Bond cleavage can lead to activation, propagation, or inactivation of a biochemical process. Control of proteolytic reactions is complex and, in its broadest sense, embraces localization of the protease and substrate, recruitment of cofactors for the purpose of acceleration of cleavage and then, direct or indirect inhibition of the protease to terminate its action. The plethora of proteolytic reactions in hemostasis provides examples of both general and process-specific mechanisms of control, which are all needed to ensure effective coordination. The proteolytic regulation of von Willebrand factor (VWF) function by its cleaving protease, ADAMTS13, falls into the latter category (ie, process-specific control), as it has certain unique features that set it apart from other hemostatic reactions. VWF is a large adhesive glycoprotein, necessary for initial platelet tethering and subsequent platelet adhesion. 1 It is a multiadhesive protein that can interact with cell surface, extracellular matrix, and plasma protein ligands through specific domain binding sites. [2][3][4][5][6] VWF is synthesized as a multimeric protein, which is central to its physiologic role. VWF function as a vessel wall damage sensor and initiator of primary hemostasis is highly dependent on its multimeric size. 7 The larger VWF multimers in plasma are the most hemostatically reactive not only because they contain more ligand binding sites, but also because they are more conformationally responsive to vascular shear forces. 1 In circulation, a first level of functional control of VWF is provided...

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Section: Adamts13 Recognition Of Globular Vwfsupporting

confidence: 67%

mentioning

confidence: 99%

Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor

Crawley

Groot

Xiang

et al. 2011

Blood

256

246

View full text Add to dashboard Cite

show abstract

“…Although the decorin protein core contains 10 LRRs similar to those present in the GPIbα subunit of the platelet receptor for VWF, it does not seem to play a major role in VWF binding. On the other hand, the finding that the decorin GAG chain fully supports interaction with VWF is in line with the reported ability of VWF to interact with heparin [7,8]. This interaction, whose biological significance is largely unclear, has been generally considered a circumstantial evidence for the ability of VWF to interact with proteoglycans containing sulfated disaccharides, although this has never been experimentally confirmed.…”

Section: Discussionsupporting

confidence: 70%

“…These results suggest that decorin and heparin may share common binding sites on the VWF molecule. Since a major heparin binding site is located in the A1 domain of VWF [8,9], we then ascertained whether this domain was involved in the interaction with decorin. Fig.…”

Section: Resultsmentioning

confidence: 99%

Binding of von Willebrand factor to the small proteoglycan decorin

et al. 2004

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The small proteoglycan decorin plays an important role in the organisation of the extracellular matrix by binding to several components, including collagen and fibronectin. In this work, we report the dose-dependent and saturable interaction of decorin with the adhesive glycoprotein, von Willebrand factor (VWF). This interaction was mediated by the glycosaminoglycan side chain of decorin and was critically regulated by the degree of sulfation, but not by the amount of iduronic acid. Both chondroitin sulfate and dermatan sulfate, in addition to heparin, were found to bind VWF equally well. Although soluble decorin prevented VWF binding to heparin, purified VWF-A1 domain failed to interact with the proteoglycan. These results identify VWF as a new partner for the small proteoglycan, decorin, in the structural organisation of the extracellular matrix.

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“…The increment of tPA and D-dimer and the decrease of PAI-1 were thought to be due to the increase in fi brinolysis. The level of VWF at 4 h of hemodialysis was higher than the initial level due to secretion of VWF from endothelium and activated platelets [17,18] , which resulted from endothelial damage and normalization of platelet functions during dialysis. We did not observe any difference in the other hemostatic parameters of blood.…”

Section: Discussionmentioning

confidence: 99%

Hemostatic and Fibrinolytic Response to Nasal Desmopressin in Hemodialysis Patients

Ulusoy¹,

Ovalı²,

Aydin³

et al. 2004

Med Princ Pract

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Objective: To evaluate the effect of desmopressin (DDAVP) on hemostatic parameters during dialysis and in the interval between dialysis sessions. Subjects and Methods: Fifteen patients dialyzed twice weekly at least for 1 year and 15 healthy volunteers serving as a control group were enrolled in the study. Bleeding time, platelet count, prothrombin time, activated partial thromboplastin time, tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), euglobulin clot lysis time, protein C, protein S, fibrinogen, D-dimer, factor V, VII, VIII, IX, X and von Willebrand factor (VWF) values were studied at the beginning, at 2 and 4 h of dialysis with and without administration of DDAVP at a dose level of 2 µg/kg intranasally. Results: After dialysis, bleeding time shortened, PAI-1 and fibrinogen levels were lower, while VWF and D-dimer levels were higher. After DDAVP administration, bleeding time, PAI-1 levels were significantly lower (p < 0.01), while tPA, factor VIII and VWF levels increased significantly (p < 0.001). Conclusion: The findings indicate that DDAVP can be used for patients on dialysis with serious bleeding.

show abstract

Structural basis of von Willebrand factor binding to platelet glycoprotein Ib and collagen. Effects of disulfide reduction and limited proteolysis of polymeric von Willebrand factor.

Abstract: Abstractvon Willebrand factor (vWF) is a large, multimeric glycoprotein that helps platelets adhere to vascular subendothelium. Although vWF binding to platelet receptors and connective tissue constit-

Cited by 46 publications

References 47 publications

Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor

Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor

Binding of von Willebrand factor to the small proteoglycan decorin

Hemostatic and Fibrinolytic Response to Nasal Desmopressin in Hemodialysis Patients

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