Primary structure of the majorO-glycosidically linked carbohydrate unit of human von Willebrand factor

Samor, Bruno; Michalski, Jean‐Claude; Mazurier, Claudine; Goudemand, M; Waard, Pieter de; Vliegenthart, Johannes F.G.; Strecker, Gérard; Montreuil, Jean

doi:10.1007/bf01047846

Cited by 43 publications

(49 citation statements)

References 25 publications

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“…8 of the 100 -linked glycans are situated between residues 485-500 and 705-724, short regions of vWf protein backbone that are believed to be close together in the tertiary structure ( 19) residues 1,460 and 2,027 (4). Sialic acids and Gal are common constituents ofboth N-linked and 0-linked glycans, and in fact occur on at least some glycans isolated from human vWf ( 35,36). The enzymatic removal of these components will therefore introduce alterations in both classes of glycans, and at widely distributed sites.…”

Section: Resultsmentioning

confidence: 99%

O-linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b.

Carew

Quinn²,

Stoddart³

et al. 1992

J. Clin. Invest.

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By transfecting the full-length cDNA for human von Willebrand factor (vWf) into a line of Chinese hamster ovary cells with a defect in carbohydrate metabolism, we have prepared recombinant vWf specifically lacking 0-linked carbohydrates. We have compared this under-glycosylated protein to fully glycosylated recombinant vWf with respect to several structural and binding properties. vWf deficient in 0-linked glycans was synthesized, assembled into multimers, and secreted in an apparently normal manner and was not prone to degradation in the extracellular milieu. It did not differ from fully glycosylated vWf in ability to bind to heparin or to collagen type I but did interact less well with glycoprotein lb on formalin-fixed platelets. This decreased interaction was evidenced in both a lessened overall binding to platelets and in diminished capacity to promote platelet agglutination, in the presence of ristocetin. In contrast, no difference was seen in platelet binding in the presence of botrocetin. These data indicate a possible role for 0-linked carbohydrates in the vWf-glycoprotein lb interaction promoted by ristocetin and suggest that abnormalities in carbohydrate modification might contribute to the altered ristocetindependent reactivity between vWf and platelets described for some variant forms of von Willebrand disease. (J. Clin. Invest. 1992Invest. . 90:2258Invest. -2267

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Section: Resultsmentioning

confidence: 99%

O-linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b.

Carew

Quinn²,

Stoddart³

et al. 1992

J. Clin. Invest.

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“…Analyses in humans show that VWF contains approximately 24 glycosylation sites with 14 involved in N-glycan modification leading to various multiantennary N-glycan branch structures (37). In addition, VWF contains O-glycans that have sialic acid linked to the Core 1 Gal and the peptide-proximal GalNAc (38). Together, this glycan diversity encompasses two sialic acid linkage types (␣2-3 and -6) distributed on at least five different glycan branch structures.…”

Section: Discussionmentioning

confidence: 99%

Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands

Ellies

Ditto

Lévy

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

175

184

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A number of poorly characterized genetic modifiers contribute to the extensive variability of von Willebrand disease, the most prevalent bleeding disorder in humans. We find that a genetic lesion inactivating the murine ST3Gal-IV sialyltransferase causes a bleeding disorder associated with an autosomal dominant reduction in plasma von Willebrand factor (VWF) and an autosomal recessive thrombocytopenia. Although both ST3Gal-IV and ST6Gal-I sialyltransferases mask galactose linkages implicated as asialoglycoprotein receptor ligands, only ST3Gal-IV deficiency promotes asialoglycoprotein clearance mechanisms with a reduction in plasma levels of VWF and platelets. Exposed galactose on VWF was also found in a subpopulation of humans with abnormally low VWF levels. Oligosaccharide branch-specific sialylation by the ST3Gal-IV sialyltransferase is required to sustain the physiologic half-life of murine hemostatic components and may be an important modifier of plasma VWF level in humans.

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“…15,16 About a quarter of these T-antigens contain disialyl structures, indicating that the terminal galactose or N-acetylgalactosamine residues are capped with 2 rather than 1 sialic acid.…”

Section: Conclusion-wementioning

confidence: 99%

Identification of Galectin-1 and Galectin-3 as Novel Partners for Von Willebrand Factor

Saint-Lu

Oortwijn

Pegon

et al. 2012

ATVB

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Objective-Although von Willebrand factor (VWF) is a heavily glycosylated protein, its potential to associate with glycan-binding proteins is poorly investigated. Here, we explored its interaction with the glycan-binding proteins galectin-1 and galectin-3. Methods and Results-Immunofluorescence analysis using Duolink proximity ligation assays revealed that VWF colocalizes with galectin-1 and galectin-3 in endothelial cells, both before and after stimulation of endothelial cells. Moreover, galectin-1 was found along the typical VWF bundles that are released by endothelial cells. Galectin-1 and galectin-3 could be coprecipitated with VWF from plasma in immunoprecipitation assays, whereas plasma levels of galectin-1 and galectin-3 were significantly reduced in VWF-deficient mice. Binding studies using purified proteins confirmed that VWF could directly interact with both galectins, predominantly via its N-linked glycans. In search of the physiological relevance of the VWF-galectin interaction, we found that inhibition of galectins in in vitro perfusion assays was associated with increased VWF-platelet string formation, a phenomenon that was reproduced in galectin-1/galectin-3 double-deficient mice. These mice were also characterized by a more rapid formation of initial thrombi following ferric chloride-induced injury. Key Words: endothelium Ⅲ hemostasis Ⅲ platelets Ⅲ galectin Ⅲ von Willebrand factor V on Willebrand factor (VWF) is an adhesive protein that is critical to the recruitment of platelets in response to vessel injury. The majority of the circulating VWF molecules are produced in the endothelial cells, where VWF is synthesized as a single prepropolypeptide chain. Following signal peptide removal, the polypeptides are assembled into C-terminal linked pro-VWF dimers. Further processing includes proteolytic removal of the propeptide and multimerization of the molecule by intermolecular N-terminal cystine bonding, generating a pool of differentially sized multimers that may contain more than 50 subunits. An important portion of the newly synthesized VWF multimers is directed to endothelial storage organelles, Weibel-Palade (WP) bodies. Conclusion-We1,2 VWF is obligatory for the formation of WP bodies, which are indeed absent in endothelial cells isolated from VWF-deficient mice or dogs.3,4 These storage organelles also contain other proteins besides VWF, including P-selectin, osteoprotegerin, CD63, and interleukin-8. 5 Some of these proteins directly interact with VWF, which may facilitate their uptake into the WP bodies. 6,7 For other residents of the storage granules, the uptake may be the result of a more random inclusion process. 8 Following endothelial stimulation, the content of the WP bodies is released into the circulation, allowing the first encounter between VWF and circulating platelets. Indeed, VWF multimers assemble into twisted bundles and networks that form long strings along the endothelial surface. 9 These VWF strings are able to catch platelets, and these platelet-decorated strings can be vis...

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Primary structure of the majorO-glycosidically linked carbohydrate unit of human von Willebrand factor

Cited by 43 publications

References 25 publications

O-linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b.

O-linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b.

Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands

Identification of Galectin-1 and Galectin-3 as Novel Partners for Von Willebrand Factor

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