Mapping the N-glycome of human von Willebrand factor

Canis, Kevin; McKinnon, Thomas A. J.; Nowak, Agata; Haslam, Stuart M.; Panico, Maria; Morris, Howard R.; Laffan, Michael; Dell, Anne

doi:10.1042/bj20120810

Cited by 81 publications

(121 citation statements)

References 39 publications

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“…Like many proteins, VWF glycan structures are well sialylated, 97,98 suggesting that the contribution of asialoglycoprotein receptor (ASGPR) to basal VWF clearance is limited. However, age, diet, and body weight can all reduce the extent of sialylation, 99,100 consequently favoring ASGPR-mediated clearance.…”

Section: Asgprmentioning

confidence: 99%

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Pipe

Montgomery

Pratt

et al. 2016

Blood

160

166

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A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in halflife of 1.5-to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. A greater understanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII. (Blood.

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Section: Asgprmentioning

confidence: 99%

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Pipe

Montgomery

Pratt

et al. 2016

Blood

160

166

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“…2,5,6 The N-and O-linked glycans of human VWF have both been characterized and demonstrate significant heterogeneity. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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%

“…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. 7,8,11 Although substantial progress has been achieved in understanding the biosynthesis, structure, and functions of VWF, the biological mechanism(s) responsible for modulating VWF clearance from the plasma remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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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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“…The glycan structures also decorate signal and carrier molecules in serum. Follicle-stimulating hormone (Lombardi et al, 2013), luteinizing hormone (Mi et al, 2014), sex hormone-binding globulin (SumerBayraktar et al, 2012), and coagulant Factor VIII (Canis et al, 2012) are some such examples.…”

Section: Introductionmentioning

confidence: 99%

Glycosylation changes leading to the increase in size on the common core of N-glycans, required enzymes, and related cancer-associated proteins

Karaçalı¹,

İzzetoğlu²,

Deveci³

2014

Turk J Biol

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Glycan parts of glycoconjugates on the surfaces of cells regulate many kinds of interactions between the cells and their immediate environments. Alterations in glycosylation on the cancer-associated glycoproteins are responsible for changes in their molecular interactions and biological functions. Glycosylation changes occur in the core and/or at the nonreducing end of the oligosaccharide chains of N-glycans. In this review, we focus on the branching of the common core structure of N-glycans, the responsible enzyme, and the extensions of some of the branches causing size increases on the surface of tumor cells. Abnormal branching, elongation of the branches, and increasing size of the common core of N-glycans are the typical features of these changes and are related with malignant transformations. Seven N-acetylglucosaminyltransferases (GnTs) (GnT-I, GnT-II, GnT-III, GnT-IV, GnT-V, GnT-VI, and GnT-IX) and α1,6-fucosyltransferase (FUT8) initiate the new branches on the core. GnT-IV, GnT-V, and GnT-IX initiate the branches available for poly-LacNAc extensions, which are responsible for tumor progression and metastasis. GnT-III prevents the catalytic activity of GnT-II, GnT-IV, GnT-V, and FUT8 to form branching and elongation of the branches. The contributions of GnT-III and the other enzymes to the cancer progression are in conflict with each other. While GnT-III prevents cancer, the others increase metastasis. The function of FUT8 is related to signal transduction and its activity is higher in tumor tissue than in healthy tissue. The impact of glycosylation changes on some of the cancer-associated proteins (growth factor receptors, adhesion and signal molecules, CD147, TIMP-1, and matriptase) is also summarized.

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Mapping the N-glycome of human von Willebrand factor

Cited by 81 publications

References 39 publications

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

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

Glycosylation changes leading to the increase in size on the common core of N-glycans, required enzymes, and related cancer-associated proteins

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