Sequence and structure relationships within von Willebrand factor

The mucus that covers and protects the epithelium of the intestine is built around its major structural component, the gel-forming MUC2 mucin. The gel-forming mucins have traditionally been assumed to be secreted as nonattached. The colon has a twolayered mucus system where the inner mucus is attached to the epithelium, whereas the small intestine normally has a nonattached mucus. However, the mucus of the small intestine of meprin β-deficient mice was now found to be attached. Meprin β is an endogenous zinc-dependent metalloprotease now shown to cleave the N-terminal region of the MUC2 mucin at two specific sites. When recombinant meprin β was added to the attached mucus of meprin β-deficient mice, the mucus was detached from the epithelium. Similar to meprin β-deficient mice, germ-free mice have attached mucus as they did not shed the membraneanchored meprin β into the luminal mucus. The ileal mucus of cystic fibrosis (CF) mice with a nonfunctional cystic fibrosis transmembrane conductance regulator (CFTR) channel was recently shown to be attached to the epithelium. Addition of recombinant meprin β to CF mucus did not release the mucus, but further addition of bicarbonate rendered the CF mucus normal, suggesting that MUC2 unfolding exposed the meprin β cleavage sites. Mucus is thus secreted attached to the goblet cells and requires an enzyme, meprin β in the small intestine, to be detached and released into the intestinal lumen. This process regulates mucus properties, can be triggered by bacterial contact, and is nonfunctional in CF due to poor mucin unfolding.protease | von Willebrand factor | gastrointestinal tract

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“…2D and Figs. S1 and S2) (18). The cleavage at SHCLE followed the published predicted specificities, whereas the other did not (19).…”

Section: Resultssupporting

confidence: 49%

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Schutte¹,

Ermund²,

Becker‐Pauly

et al. 2014

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

170

164

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“…However, the majority of FVIII circulates in complex with its carrier protein von Willebrand factor (VWF), a multimeric glycoprotein with two critical functions in hemostasis. 11 Besides its role in platelet binding in primary hemostasis, VWF prevents premature activation of FVIII and increases FVIII half-life by preventing its degradation and clearance. 12 Recently, VWF has also been shown to play an important role in FVIII inhibitor formation.…”

Section: Introductionmentioning

confidence: 99%

von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII

et al. 2015

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It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II.

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“…A domains of the protein form globular-like structures, a series of repetitive vWC domains toward the C-terminus provide the protein with increased length and flexibility, thus facilitating the transition between compact and extended conformations under conditions of shear stress in the vasculature. 3 von Willebrand desease is a result of either quantitative or qualitative defects in the vWF. The vWF is produced in the endothelial cells and bone marrow megakaryocytes and consists of multimers that are stored in platelet alpha granules and in Weibel-Palade bodies of endothelial cells.…”

Section: Von Willebrand Factor Gene and Proteinmentioning

confidence: 99%

von Willebrand Disease in Dental Clinic: An Exclusive Case Report with Review of Literature

Aparna¹

2015

Journal of Contemporary Dentistry

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ABSTRACTvon Willebrand disease (vWD) is the most common type of autosomally inherited bleeding disorder affecting up to 1% of the world's population. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein, von Willebrand factor (vWF). Since symptoms are often mild, a significant majority of patients remain undiagnosed. In the hemostasis laboratory, the measurement of vWF antigen and ristocetin cofactor activity is key components in the diagnostic algorithm for vWD. With all forms of vWD, however, bleeding episodes can be severe and may require treatment, particularly during or following surgery or dental work. The primary care physician can and should play a role in recognizing the signs and symptoms of vWD and in referring patients for proper management. The treatment of bleeding in vWD involves the use of desmopressin and plasma-derived vWF concentrates and a variety of adjunctive agents. This article gives a detailed description of the case report on a 5-year-old boy who presented with vWD in dental clinic and also imparts the knowledge on back ground, pathophysiology, classification, diagnostic measures and treatment modalities of this fatal bleeding disorder from dental perspective.

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Sequence and structure relationships within von Willebrand factor

Abstract: In the present study, we re-annotated von Willebrand factor (VWF), assigned its entire sequence to specific modules, and related these modules to structure using electron microscopy (

Cited by 269 publications

References 41 publications

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus

von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII

von Willebrand Disease in Dental Clinic: An Exclusive Case Report with Review of Literature

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