Primary structure of a new tetraantennary glycan of the N-acetyllactosaminic type isolated from human factor VIII/von Willebrand factor

Samor, Bruno; Debray, Henri; Mazurier, Claudine; Goudemand, M; Halbeek, H. van; Vliegenthart, Johannes F.G.; Montreuil, Jean

doi:10.1111/j.1432-1033.1986.tb09750.x

Cited by 22 publications

(7 citation statements)

References 23 publications

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“…In mature VWF, ABH antigens are added to the 12 N‐linked oligosaccharide chains. At present the structures of 94% of the N‐linked oligosaccharides of bi‐, tri‐, and tetra‐antennary types are known 18,29 . It was shown that rather than being necessary for maintaining multimeric structure and platelet (PLT) aggregation directly, the carbohydrate moiety protects VWF from proteolytic degradation by ADAMTS13 and also plays a key role in VWF plasma clearance 10‐18 .…”

Section: Discussionmentioning

confidence: 99%

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Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents

et al. 2010

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Section: Discussionmentioning

confidence: 99%

“…The amount of H, A, and B antigens expressed on circulating VWF is modified by ABO(H) blood group geno‐ and phenotype, which is a major determinant of VWF antigen levels 8,9 . The carbohydrate moiety (ABH‐bearing structures of VWF) protects VWF from proteolytic degradation by ADAMTS13 and also plays a key role in VWF plasma clearance 10‐18 …”

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confidence: 99%

Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents

et al. 2010

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Section: 23mentioning

confidence: 99%

“…Different studies revealed that the pro-VWF subunit carries 17 N-linked carbohydrate structures: 4 being located in the propeptide and 13 within the mature subunit. [24][25][26] Further along the synthesis pathway, the N-linked glycans undergo maturation, whereas 10 O-linked glycans are also added. 27,28 Detailed analysis of VWF by various groups unveiled an immense variation among these carbohydrate structures, particularly among the N-linked glycans (.300 structures identified).…”

Section: Glycosylationmentioning

confidence: 99%

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Blood

330

336

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To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra-and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. (Blood. 2015;125(13): 2019-2028 Introduction von Willebrand (VW) factor (VWF) is a multimeric glycoprotein present in blood plasma, the subendothelial matrix, as well as storage granules in endothelial cells (Weibel-Palade [WP] bodies [WPBs]) and platelets (a-granules).1 Although a series of novel functional properties of VWF has recently been proposed, 2 the protein is mostly known for its contribution to the hemostatic process: it mediates platelet adhesion and aggregation at sites of vascular injury and carries coagulation factor VIII (FVIII) in the circulation. 1 Patients lacking VWF manifest a severe hemorrhagic phenotype, originating from defective formation of platelet-rich thrombi and a secondary deficiency of FVIII impairing the generation of a fibrin network. Functional and/or quantitative deficiencies of VWF are known as von Willebrand disease (VWD), a disorder affecting 0.01% to 1% of the population. 3 Quantitative deficiencies of VWF result from changes in biosynthesis, secretion, and/or clearance of the protein. In this review, we will provide an overview of the current knowledge on each of these processes and we will discuss how they can be affected by the presence of protein defects. Part I: Basics of VWF biosynthesisPrimary structure VWF is produced in endothelial cells and megakaryocytes as a single prepropolypeptide of 2813 aa. The primary sequence of VWF was reported in 1986, and rapidly the presence of repeating domain structures within the protein was recognized. 4 The different domains are arranged in the order: D1-D2-D9-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK, with the D1-D2 domains representing the propeptide and the remainder corresponding to the mature VWF subunit (Figure 1). [4][5][6] Progress in structural and bioinformatical analysis of protein structures...

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“…7,8 Monosialylated or disialylated biantennary complex-type chains constitute the most common N-linked glycans expressed on VWF. 6,7,[9][10][11] Although the O-linked glycans of VWF also demonstrate marked heterogeneity, disialyl core 1 structures account for ;70% of the total population. 8,12 Importantly, although the majority of its glycans are capped by negatively charged sialic acid, 7,13 VWF is unusual in that a minority of both N-linked and O-linked carbohydrate chains express terminal ABO(H) blood group determinants.…”

Section: Introductionmentioning

confidence: 99%

N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

Chion

O’Sullivan

Drakeford

et al. 2016

Blood

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Key Points• The A1 domain of VWF contains a cryptic binding site that plays a key role in regulating macrophage binding and clearance.• The N-linked glycans presented at N1515 and N1574 within the A2 domain of VWF modulate macrophage-mediated clearance.Enhanced von Willebrand factor (VWF) clearance is important in the etiology of von Willebrand disease. However, the molecular mechanisms underlying VWF clearance remain poorly understood. In this study, we investigated the role of VWF domains and specific glycan moieties in regulating in vivo clearance. Our findings demonstrate that the A1 domain of VWF contains a receptor-recognition site that plays a key role in regulating the interaction of VWF with macrophages. In A1-A2-A3 and full-length VWF, this macrophage-binding site is cryptic but becomes exposed following exposure to shear or ristocetin. Previous studies have demonstrated that the N-linked glycans within the A2 domain play an important role in modulating susceptibility to ADAMTS13 proteolysis. We further demonstrate that these glycans presented at N1515 and N1574 also play a critical role in protecting VWF against macrophage binding and clearance. Indeed, loss of the N-glycan at N1515 resulted in markedly enhanced VWF clearance that was significantly faster than that observed with any previously described VWF mutations. In addition, A1-A2-A3 fragments containing the N1515Q or N1574Q substitutions also demonstrated significantly enhanced clearance. Importantly, clodronate-induced macrophage depletion significantly attenuated the increased clearance observed with N1515Q and N1574Q in both full-length VWF and A1-A2-A3.Finally, we further demonstrate that loss of these N-linked glycans does not enhance clearance in VWF in the presence of a structurally constrained A2 domain. Collectively, these novel findings support the hypothesis that conformation of the VWF A domains plays a critical role in modulating macrophage-mediated clearance of VWF in vivo. (Blood. 2016;128(15):1959-1968

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Primary structure of a new tetraantennary glycan of the N-acetyllactosaminic type isolated from human factor VIII/von Willebrand factor

Cited by 22 publications

References 23 publications

Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents

Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

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