The pro-polypeptide of von Willebrand factor is required for the formation of a functional factor VIII-binding site on mature von Willebrand factor

Leyte, Anja; Voorberg, Jan; Schijndel, Harm B. van; Duim, Birgitta; Pannekoek, Hans; Mourik, Jan A. van

doi:10.1042/bj2740257

Cited by 35 publications

(20 citation statements)

References 47 publications

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“…In a later study, Bendetowicz et al (28) showed that the VWF variant that lacks the propeptide does bind FVIII, albeit with a reduced affinity. The apparent discrepancy between these studies has been attributed to the fact that the VWF variant that does not bind FVIII comprises an additional alanine before Ser-764 at its N terminus (28,35). Our study has shown that a native N terminus, which starts with Ser-764, is critical for FVIII binding.…”

Section: Journal Of Biological Chemistry 397mentioning

confidence: 43%

“…It has been suggested that a VWF variant that lacks the propeptide does not bind to FVIII at all. As the propeptide mediates dimerization of the N-terminal side of VWF, it was proposed that proper dimerization is a prerequisite for effective FVIII binding (35). In a later study, Bendetowicz et al (28) showed that the VWF variant that lacks the propeptide does bind FVIII, albeit with a reduced affinity.…”

Section: Journal Of Biological Chemistry 397mentioning

confidence: 99%

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Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Castro-Núñez

Bloem

Boon-Spijker

et al. 2013

Journal of Biological Chemistry

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Background: von Willebrand factor (VWF) protects factor VIII (FVIII) from rapid clearance and degradation. Results: Mass spectrometric footprinting revealed that FVIII protects Lys-773 and the N-terminal Ser-764 of VWF from chemical modification. VWF(S764A) showed increased and VWF(K773A) showed decreased FVIII binding. Conclusion:The N terminus of VWF is critical for FVIII binding. Significance: This study sheds new light on the mechanism of FVIII-VWF complex assembly.

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Section: Journal Of Biological Chemistry 397mentioning

confidence: 43%

Section: Journal Of Biological Chemistry 397mentioning

confidence: 99%

Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Castro-Núñez

Bloem

Boon-Spijker

et al. 2013

Journal of Biological Chemistry

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“…Furthermore, a point riiutation at residue 91 has been reported in two patients with defective FVIIIhWF interaction [23,24]. Finally, it has been demonstrated that the propolypeptide of vWF is required for the formation of a functional FVIII-binding site on mature vWF [25]; this indicates that this FVIII binding property of vWF may be affected also by mutations located outside of the FVIIIbinding domain.…”

Section: Discussionmentioning

confidence: 95%

Further evidence for recessive inheritance of von willebrand disease with abnormal binding of von willebrand factor to factor VIII

et al. 1992

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A new family with a bleeding diathesis and FVIII deficiency secondary to abnormal binding of von Willebrand factor (vWF) to factor VIII (FVIII) is described. Two propositi of this family, an 18-year-old male and a 33-year-old female, both with a history of epistaxis, bruising, bleeding from the gums, epistaxis, hemarthrosis, and hematoma, were analyzed. Also additional members of the same family with no bleeding history were also studied. The propositi showed normal vWF activities, low FVIII activity; one of them had been diagnosed as having hemophilia A and the other was a hemophilia A carrier. Both showed a very poor response to treatment with FVIII concentrates and desmopressin (DDAVP) but a good clinical response to cryoprecipitate. APTT was prolonged and no inhibitory activity was noticeable in their plasmas. Thirty-five units per kilogram body weight of Hemofil M was infused to both propositi and FVIII reached basal level within 60 minutes of the infusion. No FVIII response at all was observed in the female after intravenous DDAVP administration. However, the male who received the infusion of 35 U/kg body weight of Humate-P achieved a normal FVIII level that was maintained for 12 hours. Multimeric analysis of vWF was normal in all the members studied. Von Willebrand factor domain for FVIII binding was assayed in the two propositi and in six other members of the same family by using a non-isotopic and sensitive method, a modification of the one previously described, using the Hemofil M concentrate as exogenous FVIII. The data obtained showed that both propositi had similar binding to that observed by using plasma of a patient with severe von Willebrand disease. Furthermore, five siblings had a decreased binding of vWF to FVIII, when compared with plasma from normal individuals or patients with hemophilia A. We also observed that, for screening purpose, the ratio of bound FVIII/immobilized vWF (at saturation of the anti-vWF and offering of 1 U/ml of exogenous FVIII) distinguished two levels of abnormality (normal range 0.70-1.15, propositi 0.004-0.007, and remaining members affected 0.25-0.42). The most probable explanation is that the propositi are homozygous or double heterozygous, the other five siblings affected being heterozygous for a recessive vWF defect. This more accessible assay presented here may be of help in routine analysis for diagnosing this type of von Willebrand disease, which has important implications for therapy and genetic counseling.

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“…Recent evidence from animal experiments, upon administration of rvWF precursor molecules, suggests the presence of a mechanism for extracellular propeptide removal also (Turecek et al, in press). Despite the necessity of the propeptide for vWF multimerisation (Leyte et al, 1991;Wise et al, 1991), which in turn is believed to be essential for functional activity, its subsequent removal is mandatory to enable vWF to interact with factor VIII.…”

Section: Von Willebrand Factor Propeptide Removal By Full Length Furinmentioning

confidence: 99%

Novel Frontiers in the Production of Compounds for Biomedical Use

Broekhoven¹,

Shapiro²,

Anne³

2002

Focus on Biotechnology

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COLOPHON Focus onBiotechnology is an open-ended series of reference volumes produced for Kluwer Academic Publishers BV in co-operation with the Branche Belge de la Société de Chimie Industrielle a.s.b.l.The initiative has been taken in conjunction with the Ninth European Congress on Biotechnology.The present book entitled "Novel Frontiers in the Production of Compounds for Biomedical Uses" can perhaps be placed in its best perspective by the Shakespearean character in The Tempest who exclaimed" What's past is prologue". Indeed, this compilation of some of the outstanding presentations in the field of biomedicine made at the 9 th European Congress on Biotechnology (Brussels, Belgium, July 11-15, 1999) not only reflects the achievements of the recent past, but provides a privileged glimpse of the biotechnology that is emerging in the first decade of the new Millennium.It is becoming increasingly apparent that biotechnology is offering biomedicine novel approaches and solutions to develop a sorely needed new generation of biopharmaceuticals. This is all the more necessary because in recent years, new diseases have emerged with extraordinary lethality in all corners of the globe, while age-related chronic illnesses have filled the gap wherever biomedicine has made successful inroads. The rise of antibiotic resistance also poses major threats to public health. Thus, as disease patterns evolve, the rational development of new drugs is becoming urgent, not only for the clinical outcome of patients, but also in optimising the allocation of scarce health care resources through the use of cost-effective productions methods. It is in response to all these challenges that biotechnology offers new strategies that go beyond the more traditional approaches.By the mid-1990's, the number of recombinant products approved annually for therapeutic use reached double digits. With the advent of the genomics revolution. coupled with proteomics, bioinformatics, high-throughput screening, and microelectronics, the number of potential bioproducts entering clinical trials will surely grow almost exponentially. The improved availability of structural and functional biochemical information, together with rational drug design, will also help fill the drug development pipeline. And it should certainly not be forgotten that the increasing demand for recombinant compounds necessitates improved production systems.In order to better focus on the challenges at hand, the Editors have striven to adopt an integrative approach by selecting contributions linking genomics with bacterial resistance, antibiotics with improved production strategies, optimised production approaches with chemical development programs, chemical modifications with new antibody derivatives and biomaterials, the relation between bioartificial organs and xenotransplantation, apoptosis and process biotechnology, etc. It should be readily apparent from these chapters that the development of truly novel compounds for biomedical use not only requires leading-edge science and technolog...

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The pro-polypeptide of von Willebrand factor is required for the formation of a functional factor VIII-binding site on mature von Willebrand factor

Cited by 35 publications

References 47 publications

Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII

Further evidence for recessive inheritance of von willebrand disease with abnormal binding of von willebrand factor to factor VIII

Novel Frontiers in the Production of Compounds for Biomedical Use

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