The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF

Rosenberg, Jonathan B.; Haberichter, Sandra L.; Jozwiak, Mary A.; Vokac, Elizabeth A.; Kroner, Philip A.; Fahs, Scot A.; Kawai, Yohko; Montgomery, Robert R.

doi:10.1182/blood-2002-03-0789

Cited by 59 publications

(82 citation statements)

References 37 publications

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“…10,15,37 Several mutations in VWF disrupt multimerization but not regulated storage. 12,16,17 The lack of N528S granular storage is rather distinctive in this regard, although regulated storage has yet to be examined for the majority of the many reported mutations.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] VWFpp is required for normal VWF multimer assembly and mutations in VWFpp often result in multimerization defects. 12,13 Our previous studies have demonstrated that VWF storage is initiated by VWFpp: VWFpp contains the "signal" for trafficking to granules and secondarily cotraffics mature VWF by virtue of a noncovalent association. 14,15 However, VWF granular storage and multimerization have also been shown to be independent processes: multimerization is not necessary for granular storage.…”

Section: Introductionmentioning

confidence: 99%

“…14,15 However, VWF granular storage and multimerization have also been shown to be independent processes: multimerization is not necessary for granular storage. 12,[15][16][17] Here we report the characterization of a Turkish consanguineous family diagnosed with type 2A VWD. Patient studies indicate defective regulated storage of VWF in both platelets and endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

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The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

Haberichter

Budde²,

Obser

et al. 2010

Blood

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We characterized a consanguineous Turkish family suffering from von Willebrand disease (VWD) with significant mucocutaneous and joint bleeding. The relative reduction of large plasma von Willebrand factor (VWF) multimers and the absent VWF triplet structure was consistent with type 2A (phenotype IIC) VWD. Surprisingly, platelet VWF was completely deficient of multimers beyond the VWF protomer, suggesting defective ␣-granular storage of larger multimers. Patients were nearly unresponsive to desmopressin acetate, consistent with a lack of regulated VWF release from endothelial cell Weibel-Palade bodies, suggesting defective storage also in endothelial cells. We identified an N528S homozygous mutation in the VWF propeptide D2 domain, predicting the introduction of an additional N-glycosylation site at amino acid 526 in close vicinity to a "CGLC" disulphide isomerase consensus sequence. Expression studies in mammalian cells demonstrated that N528S-VWF was neither normally multimerized nor trafficked to storage granules. However, propeptide containing the N528S mutation trafficked normally to storage granules. Our data indicate that the patients' phenotype is the result of defective multimerization, storage, and secretion. In addition, we have identified a potentially novel pathogenic mechanism of VWD, namely a transportation and storage defect of mature VWF due to defective interaction with its transporter, the mutant propeptide. (Blood. 2010;115(22): 4580-4587)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

Haberichter

Budde²,

Obser

et al. 2010

Blood

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“…The intimate relationship between multimerisation and tubulation, both requiring an interaction of the pro-peptide with the mature protein, may explain why mutations affecting multimerisation can also affect tubulation. For example the clinically significant point mutation within the pro-peptide Y87S, which reduces multimerisation, also reduces WPB elongation when overexpressed against a background of wild-type VWF in HUVECs (Haberichter et al, 2005;Michaux et al, 2006a;Rosenberg et al, 2002). Although it is the storage of VWF as proteinacious tubules within the WPBs, rather than multimerisation, that is responsible for the characteristic elongated shape of the VWF organelle (Michaux et al, 2006a;Wagner et al, 1991), it is very hard to see how such tubules can be assembled from dimers, and much further work in this area is needed.…”

Section: Introductionmentioning

confidence: 99%

Formation and function of Weibel-Palade bodies

Metcalf,

Nightingale,

Zenner

et al. 2008

Journal of Cell Science

139

140

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Weibel-Palade bodies (WPBs) are secretory organelles used for post-synthesis storage in endothelial cells that can, very rapidly, be triggered to release their contents. They carry a variety of bioactive molecules that are needed to mount a rapid response to the complex environment of cells that line blood vessels. They store factors that are essential to haemostasis and inflammation, as well as factors that modulate vascular tonicity and angiogenesis. The number of WPBs and their precise content vary between endothelial tissues, reflecting their differing physiological circumstances. The particular functional demands of the highly multimerised haemostatic protein von Willebrand Factor (VWF), which is stored in WPBs as tubules until release, are responsible for the cigar shape of these granules. How VWF tubules drive the formation of these uniquely shaped organelles, and how WPB density increases during maturation, has recently been revealed by EM analysis using high-pressure freezing and freeze substitution. In addition, an AP1/clathrin coat has been found to be essential to WPB formation. Following recruitment of cargo at the TGN, there is a second wave of recruitment that delivers integral and peripheral membrane proteins to WPBs, some of which is AP3 dependent.

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“…It is known that vWF plays a critical role in maintaining hemostasis by controlling the assembly of FVIII [25]. To evaluate the binding of FVIII to human plasmavWF and TG pig milk-rhvWF, we measured the capture of FVIII by 200 ng/ml of rhvWF bound to plates.…”

Section: Purification and Analysis Of Rhvwf In Milkmentioning

confidence: 99%

Production of Recombinant Human Von Willebrand Factor in the Milk of Transgenic Pigs

Lee

Kim

et al. 2009

Journal of Reproduction and Development

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Abstract. Von Willebrand factor (vWF), a large multimeric glycoprotein present in blood plasma, is a blood protein of the coagulation system. It is defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura-hemolytic uremic syndrome and heyde's syndrome. We have developed a line of transgenic swine harboring recombinant human von Willebrand factor (rhvWF) cDNA through microinjection of fertilized one-cell pig zygotes. Expression of rhvWF in the mammary gland and secretion of rhvWF into the milk of the transgenic swine were confirmed by immunohistochemical and western blot analyses, respectively, and rhvWF proteins were detected in milk from all lactating founder females at concentrations that were 28-to 56-folds greater than that in circulating human plasma. The amino acid sequence of rhvWF protein in the transgenic pig milk matched that of vWF produced from human blood plasma. This study provides evidence that production of rhvWF from transgenic pig milk is a potentially valuable technology and can be used as a cost-effective alternative in clinical applications. on Willebrand factor (vWF or factor VIII-related antigen)-the deficiency of which causes von Willebrand disease (vWD), the most common inherited bleeding disorder-is constitutively produced in the endothelium, megakaryocytes and subendothelial connective tissue as a large multimeric glycoprotein circulating in blood plasma [1,2]. It is also involved in a large number of other diseases, including thrombotic thrombocytopenic purpura-hemolytic uremic syndrome and heyde's syndrome [3,4], mediates platelet adhesion to sites of vascular injury by binding to specific platelet membrane glycoproteins in a closely regulated manner and functions as a carrier protein for blood clotting factor VIII (FVIII) [5]. In the circulation, vWF mainly functions by binding to other proteins, particularly FVIII, during the process of coagulation, and the absence of this interaction causes rapid degradation of vWF. In regard to the apparent role of vWF in high shear stress, vWD deficiency leads to a tendency to bleed, most apparently in tissues with high blood flow in narrow vessels [2]. The basic vWF monomer is a 2,050 amino acid protein and is assembled via identical 250-kDa subunits into disulfide-linked multimers that may vary between 2 and >20; thus, the molecular mass of the heterogeneously sized vWF protein circulating in plasma ranges from 5 × 10 5 Da to more than 5 × 10 6 Da [1, 2]. The development of a method for production of a highly purified protein on an economically large scale is one of the targets of modern animal biotechnology research. Gordon et al. were the first to attempt to produce recombinant proteins in the milk of transgenic (TG) mice [6]; since then, modification of phenotypic properties became possible [7]. Of the transgenic technologies employing domestic animals that have been developed over the last decade, one of the most popular applications has been the generation of an...

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The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF

Cited by 59 publications

References 37 publications

The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF

Formation and function of Weibel-Palade bodies

Production of Recombinant Human Von Willebrand Factor in the Milk of Transgenic Pigs

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